Nitrosated and nitrosylated proton pump inhibitors, compositions and methods of use

ABSTRACT

The present invention describes novel nitrosated and/or nitrosylated proton pump inhibitor compounds, and novel compositions comprising at least one proton pump inhibitor compound that is optionally substituted with at least one NO and/or NO 2  group, and, optionally, at least one compound that donates, transfers, or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase, and/or at least one nonsteroidal antiinflammatory drug, selective COX-2 inhibitor, antacid, bismuth-containing reagent, acid-degradable antibacterial compound, and mixtures thereof. The present invention also provides methods for treating and/or preventing gastrointestinal disorders; facilitating ulcer healing; decreasing the recurrence of ulcers; improving gastroprotective properties, anti- Helicobacter pylon  properties or antacid properties of proton pump inhibitors; decreasing or reducing the gastrointestinal toxicity associated with the use of nonsteroidal antiinflammatory compounds; treating  Helicobacter pylori  and viral infections. The compounds and/or compositions of the present invention can also be provided in the form of a pharmaceutical kit.

RELATED APPLICATIONS

This application is a divisional under 35 USC § 121 of U.S. applicationSer. No. 09/512,829, filed Feb. 25, 2000, issued as U.S. Pat. No.6,852,739, that claims priority under 35 Usc § 119 to U.S. ProvisionalApplication No. 60/122,111 filed Feb. 26, 1999.

FIELD OF THE INVENTION

The present invention describes novel nitrosated and/or nitrosylatedproton pump inhibitor compounds, and novel compositions comprising atleast one proton pump inhibitor compound that is optionally substitutedwith at least one NO and/or NO₂ group, and, optionally, at least onecompound that donates, transfers or releases nitric oxide, stimulatesendogenous synthesis of nitric oxide, elevates endogenous levels ofendothelium-derived relaxing factor or is a substrate for nitric oxidesynthase, and/or at least one nonsteroidal antiinflammatory drug,selective COX-2 inhibitor, antacid, bismuth-containing reagent,acid-degradable antibacterial compound, and mixtures thereof. Thepresent invention also provides methods for treating and/or preventinggastrointestinal disorders; facilitating ulcer healing; decreasing therecurrence of ulcers; improving gastroprotective properties,anti-Helicobacter pylori properties or antacid properties of proton pumpinhibitors; decreasing or reducing the gastrointestinal toxicityassociated with the use of nonsteroidal antiinflammatory compounds;treating Helicobacter pylori and viral infections. The compounds and/orcompositions of the present invention can also be provided in the formof a pharmaceutical kit.

BACKGROUND OF THE INVENTION

The proton pump, located in the apical membrane of the parietal cell, isresponsible for the secretion of acid in the stomach when it isstimulated by the enzyme adenosine triphosphate (H⁺, K⁺)-ATPase. Protonpump inhibitors are a class of anti-secretory compounds used in themanagement of gastrointestinal disorders. They suppress gastric acidsecretion by the specific inhibition of the (H⁺, K⁺)-ATPase enzymesystem at the secretory surface of the gastric parietal cell.

A family of substituted benzimidazoles have been developed as specificproton pump inhibitors. Two of these compounds, omeprazole andlansoprazole, are used clinically in the United States. Structurallythey contain a sulfinyl group bridging between substituted benzimidazoleand pyridine rings. At a neutral pH, omeprazole and lansoprazole arechemically stable, are weak bases, are lipid-soluble, and do not showany inhibitory activity. Once these compounds reach the parietal cellsand diffuse into the secretory canaliculi, they become protonated. Theprotonated compounds rearrange to form sulfenic acid and then asulfenamide. The latter interacts covalently with sulfhydryl groups atcritical sites in the extracellular (luminal) domain of the membranespanning (H⁺, K⁺)-ATPase. Inhibition occurs when two molecules of theinhibitor are bound per molecule of the enzyme. The specificity of theseproton pump inhibitors arises from the selective distribution of the(H⁺, K⁺)-ATPase, the acid-catalyzed rearrangement of the compounds togenerate the active inhibitor, and the trapping of the protonatedcompound and the cationic sulfenamide within the acidic canaliculi andadjacent to the target enzyme.

Omeprazole and lansoprazole are typically administered orally asdelay-release capsules. The compounds are stable at a neutral pH, butare destroyed by gastric acid. Therefore, if the integrity of thegelatin-coated capsule is destroyed in any way and the patient swallowsthe enteric-coated grains, the neutral pH in the mouth and the esophaguswill break down the microencapsulation, and the compounds will bedegraded by the gastric acid in the stomach. The delay release capsules,when appropriately taken, release the omeprazole and lansoprazole afterthe granules leave the stomach.

Despite their good anti-secretory properties, proton pump inhibitors arenot unanimously recognized as gastroprotective agents. In addition,there is a high relapse rate associated with treating gastrointestinaldisorders with proton pump inhibitors as they do not eliminateHelicobacter pylori (Campylobacter pylori), the bacteria responsible forpeptic ulcer disease, gastric lymphoma and adenocarcinoma. U.S. Pat.Nos. 5,599,794 and 5,629,305 describe the administration of proton pumpinhibitors in combination with acid-degradable antibacterial compoundsfor the treatment of infections caused by Helicobacter pylori.

A variety of adverse reactions have been ascribed to proton pumpinhibitors, such as omeprazole and lansoprazole, reflecting, in part,the very large number of patients who have been treated with thesedrugs. The incidence of adverse reactions is low, and the adversereactions are generally minor. Due to the profound reduction in gastricacidity, there tends to be an increased secretion of gastrin. Hence,patients who take therapeutic doses of omeprazole and lansoprazole havemodest hypergastrinemia. Prolonged administration of high doses of thedrugs can cause hyperplasia of oxyntic mucosal cells.

The most common side effects of proton pump inhibitors, such asomeprazole and lansoprazole, are nausea, diarrhea, abdominal colic, andcentral nervous system effects such as headaches and dizziness.Occasionally skin rashes and transient elevations of plasma activitiesof hepatic aminotransferase have been reported. The drugs can alsoresult in bacterial overgrowth in the gastrointestinal tract and thedevelopment of nosocomial pneumonia.

There is a need in the art for proton pump inhibitors that have improvedgastroprotective properties, decrease the recurrence of ulcers,facilitate ulcer healing and that can be used at low dosages. Thepresent invention is directed to these, as well as other, importantends.

SUMMARY OF THE INVENTION

The present invention provides proton pump inhibitors to which is linkedat least one NO and/or NO₂ group (i.e., nitrosylated and/or nitrosated).The proton pump inhibitors can be, for example, substitutedbenzimidazoles and substituted azabenzimidazoles, including, forexample, omeprazole, pantoprazole, rabeprazole, leminoprazole,lansoprazole, timoprazole, tenatoprazole, disulprazole, esomeprazole, RO18-5362 and IY 81149. The present invention also provides compositionscomprising such compounds in a pharmaceutically acceptable carrier.

Another aspect of the invention provides compositions comprising atleast one proton pump inhibitor, that is optionally substituted with atleast one NO and/or NO₂ group (i.e., nitrosylated and/or nitrosated),and at least one compound that donates, transfers or releases nitricoxide and/or stimulates endogenous production of nitric oxide (NO) orendothelium-derived relaxing factor (EDRF) in vivo and/or is a substratefor nitric oxide synthase. The present invention also providescompositions comprising such compounds in a pharmaceutically acceptablecarrier.

Yet another aspect of the present invention provides methods fortreating gastrointestinal disorders, methods for improving thegastroprotective properties, anti-Helicobacter properties and antacidproperties of proton pump inhibitors, methods for facilitating ulcerhealing and methods for decreasing the rate of recurrence of ulcers in apatient in need thereof comprising administering to the patient at leastone proton pump inhibitor that is substituted with at least one NOand/or NO₂ group, or by administering to the patient at least one protonpump inhibitor, that is optionally substituted with at least one NOand/or NO₂ group, and at least one compound that donates, transfers orreleases nitric oxide and/or stimulates endogenous production of nitricoxide or EDRF in vivo. The proton pump inhibitor, that is optionallysubstituted with at least one NO and/or NO₂ group, and nitric oxidedonor can be administered separately or as components of the samecomposition in one or more pharmaceutically acceptable carriers.

The present invention also provides methods to decrease or reversegastrointestinal toxicity resulting from the administration ofnonsteroidal antiinflammatory drugs (NSAIDs) and/or selective COX-2inhibitors, and methods to facilitate ulcer healing resulting from theadministration of NSAIDs and/or selective COX-2 inhibitors, in a patientin need thereof by administering the compounds and/or compositions ofthe present invention. The present invention also provides methods totreat infections caused by Helicobacter pylori and/or viruses inpatients in need thereof by administering the compounds and/orcompositions of the present invention.

These and other aspects of the present invention are described in detailherein.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the gastric lesion scores of (a) vehicle alone (open bar,n=10); (b) lanzoprazole in vehicle (stripped bar, n=10); and (c) example2 (nitrosylated lanzoprazole) in vehicle (checked bar, n=9).Lanzoprazole at 200 μmol/kg did not significantly inhibit the formationof gastric lesions relative to vehicle alone. Example 2 (nitrosylatedlanzoprazole) at 200 μmol/kg inhibited the formation of gastric lesionsrelative to vehicle alone (p<0.05) and lanzoprazole (p<0.05).

DETAILED DESCRIPTION OF THE INVENTION

As used throughout the disclosure, the following terms, unless otherwiseindicated, shall be understood to have the following meanings.

“Gastrointestinal disorder” refers to any disease or disorder of theupper and lower gastrointestinal tract of a patient including, forexample, inflammatory bowel disease, Crohn's disease, irritable bowelsyndrome, ulcerative colitis, peptic ulcers, stress ulcers, bleedingpeptic ulcers, duodenal ulcers, infectious enteritis, colitis,diverticulitis, gastric hyperacidity, dyspepsia, gastroparesis,Zollinger-Ellison syndrome, gastroesophageal reflux disease,Helicobacter Pylori associated disease, short-bowel (anastomosis)syndrome, hypersecretory states associated with systemic mastocytosis orbasophilic leukemia and hyperhistaminemia that result, for example, fromneurosurgery, head injury, severe body trauma or burns.

“Upper gastrointestinal tract” refers to the esophagus, the stomach, theduodenum and the jejunum.

“Lower gastrointestinal tract” refers to the ileum, the colon, the cecumand the rectum.

“Ulcers” refers to lesions of the upper gastrointestinal tract liningthat are characterized by loss of tissue. Such ulcers include gastriculcers, duodenal ulcers and gastritis.

“Viral infection” refers to both RNA and DNA viral infections. The RNAviral infections include, but are not limited to, orthomyxoviridae,paramyxoviridae, picomaviridae, rhabdoviridae, coronavaridae,togaviridae, bunyaviridae, arenaviridae and reteroviridae. The DNA viralinfections include, but are not limited to, adenoviridae, proxviridae,papovaviridae, herpetoviridae and herpesviridae. The most preferableviral infections are those of the herpetoviridae family, such as, forexample, herpes simplex viruses HSV-1 and HSV-2, cytomegalovirus (CMV),herpes varicella-zoster (VZV), Epstein-Barr (EBV), HHV6, HHV7,pseudorabies and rhinotracheitis, and the like.

“Proton pump inhibitor” refers to any compound that reversibly orirreversibly blocks gastric acid secretion by inhibiting the H⁺/K⁺-ATPase enzyme system at the secretory surface of the gastric parietal cell.

“NSAID” refers to a nonsteroidal anti-inflammatory compound or anonsteroidal anti-inflammatory drug. NSAIDs inhibit cyclooxygenase, theenzyme responsible for the biosyntheses of the prostaglandins andcertain autocoid inhibitors, including inhibitors of the variousisozymes of cyclooxygenase (including but not limited tocyclooxygenase-1 and -2), and as inhibitors of both cyclooxygenase andlipoxygenase.

“Cyclooxygenase-2 (COX-2) inhibitor” refers to a compound thatselectively inhibits the cyclooxygenase-2 enzyme over thecyclooxygenase-1 enzyme. Preferably, the compound has a cyclooxygenase-2IC₅₀ of less than about 0.5 μM, and also has a selectivity ratio ofcyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at least50, and more preferably of at least 100. Even more preferably, thecompound has a cyclooxygenase-1 IC₅₀ of greater than about 1 μM, andmore preferably of greater than 20 μM. The compound can also inhibit theenzyme, lipoxygenase.

“Patient” refers to animals, preferably mammals, more preferably humans.

“Transdermal” refers to the delivery of a compound by passage throughthe skin and into the blood stream.

“Transmucosal” refers to delivery of a compound by passage of thecompound through the mucosal tissue and into the blood stream.

“Penetration enhancement” or “permeation enhancement” refers to anincrease in the permeability of the skin or mucosal tissue to a selectedpharmacologically active compound such that the rate at which thecompound permeates through the skin or mucosal tissue is increased.

“Carriers” or “vehicles” refers to carrier materials suitable forcompound administration and include any such material known in the artsuch as, for example, any liquid, gel, solvent, liquid diluent,solubilizer, or the like, which is non-toxic and which does not interactwith any components of the composition in a deleterious manner.

“Nitric oxide adduct” or “NO adduct” refers to compounds and functionalgroups which, under physiological conditions, can donate, release and/ordirectly or indirectly transfer any of the three redox forms of nitrogenmonoxide (NO⁺, NO⁻, NO.), such that the biological activity of thenitrogen monoxide species is expressed at the intended site of action.

“Nitric oxide releasing” or “nitric oxide donating” refers to methods ofdonating, releasing and/or directly or indirectly transferring any ofthe three redox forms of nitrogen monoxide (NO⁺, NO⁻, NO.), such thatthe biological activity of the nitrogen monoxide species is expressed atthe intended site of action.

“Nitric oxide donor” or “NO donor” refers to compounds that donate,release and/or directly or indirectly transfer a nitrogen monoxidespecies, and/or stimulate the endogenous production of nitric oxide orendothelium-derived relaxing factor (EDRF) in vivo and/or elevateendogenous levels of nitric oxide or EDRF in vivo. “NO donor” alsoincludes compounds that are substrates for nitric oxide synthase.

“Alkyl” refers to a lower alkyl group, a haloalkyl group, an alkenylgroup, an alkynyl group, a bridged cycloalkyl group, a cycloalkyl groupor a heterocyclic ring, as defined herein.

“Lower alkyl” refers to branched or straight chain acyclic alkyl groupcomprising one to about ten carbon atoms (preferably one to about eightcarbon atoms, more preferably one to about six carbon atoms). Exemplarylower alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, iso-amyl, hexyl, octyl,and the like.

“Haloalkyl” refers to a lower alkyl group, an alkenyl group, an alkynylgroup, a bridged cycloalkyl group, a cycloalkyl group or a heterocyclicring, as defined herein, to which is appended one or more halogens, asdefined herein. Exemplary haloalkyl groups include trifluoromethyl,chloromethyl, 2-bromobutyl, 1-bromo-2-chloro-pentyl, and the like.

“Alkenyl” refers to a branched or straight chain C₂-C₁₀ hydrocarbon(preferably a C₂-C₈ hydrocarbon, more preferably a C₂-C₆ hydrocarbon)which can comprise one or more carbon-carbon double bonds. Exemplaryalkenyl groups include propylenyl, buten-1-yl, isobutenyl, penten-1-yl,2,2-methylbuten-1-yl, 3-methylbuten-1-yl, hexan-1-yl, hepten-1-yl,octen-1-yl, and the like.

“Alkynyl” refers to an unsaturated acyclic C₂-C₁₀ hydrocarbon(preferably a C₂-C₈ hydrocarbon, more preferably a C₂-C₆ hydrocarbon)which can comprise one or more carbon-carbon triple bonds. Exemplaryalkynyl groups include ethynyl, propynyl, butyn-1-yl, butyn-2-yl,pentyl-1-yl, pentyl-2-yl, 3-methylbutyn-1-yl, hexyl-1-yl, hexyl-2-yl,hexyl-3-yl, 3, 3-dimethyl-butyn-1-yl, and the like.

“Bridged cycloalkyl” refers to two or more cycloalkyl groups,heterocyclic groups, or a combination thereof fused via adjacent ornon-adjacent atoms. Bridged cycloalkyl groups can be unsubstituted orsubstituted with one, two or three substituents independently selectedfrom alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo,carboxyl, alkylcarboxylic acid, aryl, amidyl, ester, alkylcarboxylicester, carboxamido, alkylcarboxamido, oxo and nitro. Exemplary bridgedcycloalkyl groups include adamantyl, decahydronapthyl, quinuclidyl,2,6-dioxabicyclo[3.3.0]octane, 7-oxabycyclo[2.2.1]heptyl,8-azabicyclo[3,2,1]oct-2-enyl and the like.

“Cycloalkyl” refers to a saturated or unsaturated cyclic hydrocarboncomprising from about 3 to about 8 carbon atoms. Cycloalkyl groups canbe unsubstituted or substituted with one, two or three substituentsindependently selected from alkyl, alkoxy, amino, alkylamino,dialkylamnino, arylamino, diarylamino, alkylarylamino, aryl, amidyl,ester, hydroxy, halo, carboxyl, alkylcarboxylic acid, alkylcarboxylicester, carboxamido, alkylcarboxamido, oxo and nitro. Exemplarycycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclohexenyl, cyclohepta,1,3-dienyl, and the like.

“Heterocyclic ring or group” refers to a saturated, unsaturated cyclicor polycyclic hydrocarbon group having about 3 to about 12 carbon atoms(preferably about 4 to about 6 carbon atoms) where 1 to about 4 carbonatoms are replaced by one or more nitrogen, oxygen and/or sulfur atoms.Sulfur maybe in the thio, sulfinyl or sulfonyl oxidation state. Theheterocyclic ring or group can be fused to an aromatic hydrocarbongroup. Heterocyclic groups can be unsubstituted or substituted with one,two or three substituents independently selected from alkyl, alkoxy,amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino,hydroxy, oxo, thial, halo, carboxyl, carboxylic ester, alkylcarboxylicacid, alkylcarboxylic ester, aryl, arylcarboxylic acid, arylcarboxylicester, amidyl, ester, carboxamido, alkylcarboxamido, arylcarboxamido,sulfonic acid, sulfonic ester, sulfonamido and nitro. Exemplaryheterocyclic groups include pyrrolyl,3-pyrrolinyl,4,5,6-trihydro-2H-pyranyl, pyridinyl, 1,4-dihydropyridinyl,pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl,imidazolyl, indolyl, thiophenyl, furanyl, tetrhydrofuranyl, tetrazolyl,2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, oxazolindinyl 1,3-dioxolanyl,2,6-dioxabicyclo[3,3,0]octanyl, 2-imidazonlinyl, imidazolindinyl,2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl,1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl,4H-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl,thiomorpholinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl,1,3,5-trithianyl, benzo(b)thiophenyl, benzimidazolyl, quinolinyl, andthe like.

“Heterocyclic compounds” refer to mono- and polycyclic compoundscomprising at least one aryl or heterocyclic ring.

“Aryl” refers to a monocyclic, bicyclic, carbocyclic or heterocyclicring system comprising one or two aromatic rings. Exemplary aryl groupsinclude phenyl, pyridyl, napthyl, quinoyl, tetrahydronaphthyl, furanyl,indanyl, indenyl, indoyl, and the like. Aryl groups (including bicylicaryl groups) can be unsubstituted or substituted with one, two or threesubstituents independently selected from alkyl, alkoxy, amino,alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino,hydroxy, carboxyl, carboxylic ester, alkylcarboxylic acid,alkylcarboxylic ester, aryl, arylcarboxylic acid, arylcarboxylic ester,alkylcarbonyl, arylcarbonyl, amidyl, ester, carboxamido,alkylcarboxamido, carbomyl, sulfonic acid, sulfonic ester, sulfonamidoand nitro. Exemplary substituted aryl groups include tetrafluorophenyl,pentafluorophenyl, sulfonamide, alkylsulfonyl, arylsulfonyl, and thelike.

“Alkylaryl” refers to an alkyl group, as defined herein, to which isappended an aryl group, as defined herein. Exemplary alkylaryl groupsinclude benzyl, phenylethyl, hydroxybenzyl, fluorobenzyl,fluorophenylethyl, and the like.

“Arylalkyl” refers to an aryl radical, as defined herein, attached to analkyl radical, as defined herein.

“Cycloalkylalkyl” refers to a cycloalkyl radical, as defined herein,attached to an alkyl radical, as defined herein.

“Heterocyclicalkyl” refers to a heterocyclic ring radical, as definedherein, attached to an alkyl radical, as defined herein.

“Cycloalkenyl” refers to an unsaturated cyclic hydrocarbon having about3 to about 10 carbon atoms (preferably about 3 to about 8 carbon atoms,more preferably about 3 to about 6 carbon atoms) comprising one or morecarbon-carbon double bonds.

“Arylheterocyclic ring” refers to a bi- or tricyclic ring comprised ofan aryl ring, as defined herein, appended via two adjacent carbon atomsof the aryl ring to a heterocyclic ring, as defined herein. Exemplaryarylheterocyclic rings include dihydroindole,1,2,3,4-tetra-hydroquinoline, and the like.

“Alkoxy” refers to R₅₀O—, wherein R₅₀ is an alkyl group, as definedherein. Exemplary alkoxy groups include methoxy, ethoxy, t-butoxy,cyclopentyloxy, and the like.

“Arylalkoxy or alkoxyaryl” refers to an alkoxy group, as defined herein,to which is appended an aryl group, as defined herein. Exemplaryarylalkoxy groups include benzyloxy, phenylethoxy, chlorophenylethoxy,and the like.

“Alkoxyalkyl” refers to an alkoxy group, as defined herein, appended toan alkyl group, as defined herein. Exemplary alkoxyalkyl groups includemethoxymethyl, methoxyethyl, isopropoxymethyl, and the like.

“Alkoxyhaloalkyl” refers to an alkoxy group, as defined herein, appendedto a haloalkyl group, as defined herein. Exemplary alkoxyhaloalkylgroups include 4- methoxy-2-chlorobutyl and the like.

“Cycloalkoxy” refers to R₅₄O—, wherein R₅₄ is a cycloalkyl group or abridged cycloalkyl group, as defined herein. Exemplary cycloalkoxygroups include cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, and thelike.

“Haloalkoxy” refers to a haloalkyl group, as defined herein, to which isappended an alkoxy group, as defined herein. Exemplary haloalkyl groupsinclude 1,1,1-trichloroethoxy, 2-bromobutoxy, and the like.

“Hydroxy” refers to —OH.

“Oxo” refers to ═O.

“Oxy” refers to —O⁻R₇₇ ⁺ wherein R₇₇ is an organic or inorganic cation.

“Organic cation” refers to a positively charged organic ion. Exemplaryorganic cations include alkyl substituted ammonium cations, and thelike.

“Inorganic cation” refers to a positively charged metal ion. Exemplaryinorganic cations include Group I metal cations such as for example,sodium, potassium, and the like.

“Hydroxyalkyl” refers to a hydroxy group, as defined herein, appended toan alkyl group, as defined herein.

“Amino” refers to —NH₂.

“Nitrate” refers to —O—NO₂.

“Nitrite” refers to —O—NO.

“Thionitrate” refers to —S—NO₂.

“Thionitrite” and “nitrosothiol” refer to —S—NO.

“Nitro” refers to the group —NO₂ and “nitrosated” refers to compoundsthat have been substituted therewith.

“Nitroso” refers to the group —NO and “nitrosylated” refers to compoundsthat have been substituted therewith.

“Nitrile” and “cyano” refer to —CN.

“Halogen” or “halo” refers to iodine (I), bromine (Br), chlorine (Cl),and/or fluorine (F).

“Alkylamino” refers to R₅₀NH—, wherein R₅₀ is an alkyl group, as definedherein. Exemplary alkylamino groups include methylamino, ethylamino,butylamino, cyclohexylamino, and the like.

“Arylamino” refers to R₅₅NH—, wherein R₅₅ is an aryl group, as definedherein.

“Dialkylamino” refers to R₅₀R₅₂N—, wherein R₅₀ and R₅₂ are eachindependently an alkyl group, as defined herein. Exemplary dialkylaminogroups include dimethylamino, diethylamino, methyl propargylamino, andthe like.

“Diarylamino” refers to R₅₅R₆₀N—, wherein R₅₅ and R₆₀ are eachindependently an aryl group, as defined herein.

“Alkylarylamino” refers to R₅₀R₅₅N—, wherein R₅₀ is an alkyl group, asdefined herein, and R₅₅ is an aryl group, as defined herein.

“Aminoalkyl” refers to an amino group, an alkylamino group, adialkylamino group, an arylamino group, a diarylamino group, analkylarylamino group or a heterocyclic ring, as defined herein, to whichis appended an alkyl group, as defined herein.

“Aminoaryl” refers to an amino group, an alkylamino group, adialkylamino group, an arylamino group, a diarylamino group, analkylarylamino group or a heterocyclic ring, as defined herein, to whichis appended an aryl group, as defined herein.

“Thio” refers to —S—.

“Sulfinyl” refers to —S(O)—.

“Methanthial” refers to —C(S)—.

“Thial” refers to ═S.

“Sulfonyl” refers to —S(O)₂ ⁻.

“Sulfonic acid” refers to —S(O)₂OR₇₆, wherein R₇₆ is a hydrogen, anorganic cation or an inorganic cation.

“Alkylsulfonic acid” refers to a sulfonic acid group, as defined herein,appended to an alkyl group, as defined herein.

“Arylsulfonic acid” refers to an sulfonic acid group, as defined herein,appended to an aryl group, as defined herein

“Sulfonic ester” refers to —S(O)₂OR₅₈, wherein R₅₈ is an alkyl group, anaryl group, an alkylaryl group or an aryl heterocyclic ring, as definedherein.

“Sulfonamido” refers to —S(O)₂—N(R₅₁)(R₅₇), wherein R₅₁ and R₅₇ are eachindependently a hydrogen atom, an alkyl group, an aryl group, analkylaryl group, or an arylheterocyclic ring, as defined herein, and R₅₁and R₅₇ when taken together are a heterocyclic ring, a cycloalkyl groupor a bridged cycloalkyl group, as defined herein.

“Alkylsulfonamido” refers to a sulfonamido group, as defined herein,appended to an alkyl group, as defined herein.

“Arylsulfonamido” refers to a sulfonamido group, as defined herein,appended to an aryl group, as defined herein.

“Sulfamoyl” refers to R₅₁S(O)₂—N(R₅₇)—, wherein R₅₁ and R₅₇ are eachindependently a hydrogen atom, an alkyl group, an aryl group, analkylaryl group, or an arylheterocyclic ring, as defined herein, and R₅₁and R₅₇ when taken together are a heterocyclic ring, a cycloalkyl groupor a bridged cycloalkyl group, as defined herein.

“Alkylthio” refers to R₅₀S—, wherein R₅₀ is an alkyl group, as definedherein.

“Arylthio” refers to R₅₅S—, wherein R₅₅ is an aryl group, as definedherein.

“Cycloalkylthio” refers to R₅₄S—, wherein R₅₄ is a cycloalkyl group or abridged cycloalkyl group, as defined herein. Exemplary cycloalkylthiogroups include cyclopropylthio, cyclopentylthio, cyclohexylthio, and thelike.

“Alkylsulfinyl” refers to R₅₀—S(O)—, wherein R₅₀ is an alkyl group, asdefined herein.

“Alkylsulfonyl” refers to R₅₀—S(O)₂—, wherein R₅₀ is an alkyl group, asdefined herein.

“Arylsulfinyl” refers to R₅₅—S(O)—, wherein R₅₅ is an aryl group, asdefined herein.

“Arylsulfonyl” refers to R₅₅—S(O)₂—, wherein R₅₅ is an aryl group, asdefined herein.

“Amidyl” refers to R₅₁C(O)N(R₅₇)— wherein R₅₁ and R₅₇ are eachindependently a hydrogen atom, an alkyl group, an aryl group, analkylaryl group, or an arylheterocyclic ring, as defined herein.

“Ester” refers to R₅₁C(O)O— wherein R₅₁ is a hydrogen atom, an alkylgroup, an aryl group, an alkylaryl group, or an arylheterocyclic ring,as defined herein.

“Carbamoyl” refers to —O—C(O)N(R₅₁)(R₅₇), wherein R₅₁ and R₅₇ are eachindependently a hydrogen atom, an alkyl group, an aryl group, analkylaryl group or an arylheterocyclic ring, as defined herein, or R₅₁and R₅₇ taken together are a heterocyclic ring, a cycloalkyl group or abridged cycloalkyl group, as defined herein.

“Carboxyl” refers to —C(O)OR₇₆, wherein R₇₆ is a hydrogen, an organiccation or an inorganic cation, as defined herein.

“Carbonyl” refers to —C(O)—.

“Alkylcarbonyl” or “alkanoyl” refers to R₅₀—C(O)—, wherein R₅₀ is analkyl group, as defined herein.

“Arylcarbonyl” or “aroyl” refers to R₅₅—C(O)—, wherein R₅₅ is an arylgroup, as defined herein.

“Carboxylic ester” refers to —C(O)OR₅₈, wherein R₅₈ is an alkyl group,an aryl group, an alkylaryl group or an aryl heterocyclic ring, asdefined herein.

“Alkylcarboxylic acid” and “alkylcarboxyl” refer to an alkyl group, asdefined herein, appended to a carboxyl group, as defined herein.

“Alkylcarboxylic ester” refers to an alkyl group, as defined herein,appended to a carboxylic ester group, as defined herein.

“Arylcarboxylic acid” refers to an aryl group, as defined herein,appended to a carboxyl group, as defined herein.

“Arylcarboxylic ester” and “arylcarboxyl” refer to an aryl group, asdefined herein, appended to a carboxylic ester group, as defined herein.

“Carboxamido” refers to —C(O)N(R₅₁)(R₅₇), wherein R₅₁ and R₅₇ are eachindependently a hydrogen atom, an alkyl group, an aryl group, analkylaryl group or an arylheterocyclic ring, as defined herein, and R₅₁and R₅₇ when taken together are a heterocyclic ring, a cycloalkyl groupor a bridged cycloalkyl group, as defined herein.

“Alkylcarboxamido” refers to an alkyl group, as defined herein, appendedto a carboxamido group, as defined herein.

“Arylcarboxamido” refers to an aryl group, as defined herein, appendedto a carboxamido group, as defined herein.

“Urea” refers to —N(R₅₉)—C(O)N(R₅₁)(R₅₇) wherein R₅₁, R₅₇, and R₅₉ areeach independently a hydrogen atom, an alkyl group, an aryl group, analkylaryl group, or an arylheterocyclic ring, as defined herein, or R₅₁and R₅₇ taken together are a heterocyclic ring, a cycloalkyl group or abridged cycloalkyl group, as defined herein.

“Phosphoryl” refers to —P(R₇₀)(R₇₁)(R₇₂), wherein R₇₀ is a lone pair ofelectrons, sulfur or oxygen, and R₇₁ and R₇₂ are each independently acovalent bond, a hydrogen, a lower alkyl, an alkoxy, an alkylamino, ahydroxy or an aryl, as defined herein.

Compounds that donate, transfer or release nitric oxide species in vivohave a wide spectrum of advantages and applications. The presentinvention is based on the discovery of the effects of such compoundstogether with one or more proton pump inhibitors and/or one or moreproton pump inhibitors directly or indirectly linked with one or morenitric oxide moieties. Treatment or prevention of gastrointestinaldisorders, improved gastroprotective properties, decreased rate ofrecurrence of peptic ulcers and faster ulcer healing can be obtained bythe use of the nitrosated and/or nitrosylated proton pump inhibitors ofthe present invention. Treatment or prevention of gastrointestinaldisorders, improved gastroprotective properties, decreased rate ofrecurrence of peptic ulcers and faster ulcer healing can also beobtained by the use of one or more proton pump inhibitors, that areoptionally directly or indirectly linked with one or more nitric oxidemoieties, in conjunction with one or more compounds that donate, releaseor transfer nitric oxide or stimulate endogenous production of nitricoxide or EDRF in vivo or are substrates for nitric oxide synthase.

Proton pump inhibitors are compounds that selectively inhibit gastricacid secretion by the specific inhibition of the (H⁺, K⁺)-ATPase enzymesystem at the secretory surface of the gastric parietal cell. A nitricoxide donor is a compound that contains at least one nitric oxide adductand releases or chemically transfers a biologically active nitrogenmonoxide species.

The compounds and compositions of the present invention are novel andcan be used to treat numerous gastrointestinal diseases and disorders.Such gastrointestinal disorders include, for example, inflammatory boweldisease, Crohn's disease, irritable bowel syndrome, ulcerative colitis,peptic ulcers, stress ulcers, bleeding peptic ulcers, duodenal ulcers,infectious enteritis, colitis, diverticulitis, gastric hyperacidity,gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellisonsyndrome, gastroesophageal reflux disease, Helicobacter Pyloriassociated disease, short-bowel (anastomosis) syndrome, hypersecretorystates associated with systemic mastocytosis or basophilic leukemia andhyperhistaminemia that result, for example, from neurosurgery, headinjury, severe body trauma or burns. The compounds and compositions ofthe present invention can also be used as a pre-anesthetic medication inemergency operations to reduce the danger of aspiration of acidicgastric contents

The proton pump inhibitors used in the compounds and compositions of thepresent invention can be any of those known in the art, such as thoseexemplified herein.

Omeprazole, i.e.,5-methoxy-2((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)-sulfinyl)-1H-benzimidazole,(marketed under the trade name PRILOSEC® by Astra Merck, Wayne, Pa.) andlansoprazole, i.e.,2-(((3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl)methyl)sulfinyl)-1H-benzimidazole(marketed under the trade name PREVACID® by TAP Pharmaceutical Inc.,Deerfield, Ill.) are two of the most widely used compounds that inhibitgastric acid secretion. Other useful compounds include rabeprazole,i.e.,2-(((4-(3-methoxypropoxy)-3-methyl-2-pyridinyl)methyl)sulfinyl)-1H-benzimidazole(marketed under the trade name ACIPHEX® by Eisai, Inc.), pantoprazole,i.e.,5-(difluoromethoxy)-2-(((3,4-dimethoxy-2-pyridinyl)methyl)sulfinyl)-1H-benzimidazole,leminoprazole, timoprazole, tenatoprazole, disulprazole, esomeprazole,RO 18-5362, IY 81149. These compound do not exhibit anticholinergic orhistamine H₂-receptor antagonist properties, but suppress gastric acidsecretion by the specific inhibition of (H⁺, K⁺)-ATPase enzyme system atthe secretory surface of the gastric parietal cell. As this enzymesystem is regarded as the acid (proton) pump within the parietal cell,these substituted benzimidazoles have been characterized asgastric-acid-pump inhibitors as they block the final step of acidproduction. Although the proton pump inhibitor anti-secretory agents areeffective in treating gastrointestinal disorders, they do not have anygastroprotective properties and, in addition, there is a high recurrenceof ulcers associated with their use.

Another group of proton pump inhibitors are substituted quinolines,which include, for example,3-butyl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)-quinoline.

Other proton pump inhibitors are disclosed in, for example, U.S. Pat.Nos. 4,045,564, 4,255,431, 4,634,710, 4,758,579, 4,806,549, 4,806,550,4,818,760, 4,839,365, 4,845,118, 4,871,734, 4,873,337, 4,956,366,4,981,861, 5,114,955, 5,149,702, 5,439,917, 5,554,631, 5,665,730,5,677,302, 5,686,458, 5,703,097, 5,750,531, 5,990,311, 5,952,504 and5,945,425 and in EP 0 033 094 B1, EP 0 045 200 A1, EP 0 221041 A2, EP 0234 485 A1, EP 0 246 774 A1, EP 0 254 588 A1, EP 0 259 174 A1 and in WO89/08104, WO 92/12969, WO 95/27714, WO 97/32854, WO 98/18784, WO98/43968, WO 98/54172; the disclosures of each of which are incorporatedby reference herein in their entirety.

Several of the above contemplated proton pump inhibitors are describedmore fully in the literature, such as in Goodman and Gilman, ThePharmacological Basis of Therapeutics (9th Edition), McGraw-Hill, pages901-915 (1996); Merck Index on CD-ROM, Twelfth Edition, Version 12:1,(1996); STN Express, file phar and file registry, the disclosures ofwhich are incorporated by reference herein in their entirety.

The proton pump inhibitors of the present invention can be nitrosatedand/or nitrosylated through one or more sites such as oxygen (hydroxylcondensation), sulfur (sulfhydryl condensation), carbon and nitrogen.The proton pump inhibitor compounds that are nitrosated and/ornitrosylated in accordance with the invention and/or are included in thecompositions of the invention can be any of those known in the art,including those exemplified below.

In one embodiment, the present invention describes nitrosated and/ornitrosylated proton pump inhibitors of Formula (I) or a pharmaceuticallyacceptable salt thereof:

wherein

-   -   A is S, S(O), or S(O)₂;    -   B is —CNR₇R₇′ or nitrogen;    -   J is CH or nitrogen;    -   R₁ is a hydrogen, an alkoxy group, a lower alkyl group, or an        alkylthio group;    -   R₂ is a hydrogen, an alkoxy group, a lower alkyl group, an        alkylthio group, a haloalkoxy group, an alkoxyalkyl group,        —NR₇R₇′, —OD₁, or —SD₁; or R₂ and R₁ taken together with the        carbon chain to which they are attached form a cycloalkyl ring        or a heterocyclic ring; or R₂ and R₃ taken together with the        carbon chain to which they are attached form a cycloalkyl ring        or a heterocyclic ring;    -   R₃ and R₁₁ are each independently a hydrogen, an alkoxy group, a        lower alkyl group, or an alkylthio group; or R₃ and R₁₁ taken        together with the carbon chain to which they are attached form a        cycloalkyl ring or a heterocyclic ring;    -   R₄ and R₅ are each independently a hydrogen, an alkyl group, a        halo group, an alkoxy group, a haloalkyl group, a haloalkoxy        group, a cyano group, an aryl group, a heterocyclic ring,        —NR₇R₇′, —OD₁, or —CO₂R₁₂; or R₄ and R₅ taken together are:

wherein

-   -   R₆ is oxygen or N═O—R₇;    -   R₇ and R₇′ are each independently hydrogen, a lower alkyl group        or D; or R₇ and R₇′ taken together with the nitrogen to which        they are attached form a heterocyclic ring;    -   R₁₀ is a hydrogen; or R₁₀ and R₁ taken together with the carbon        chain to which they are attached form a cycloalkyl ring;    -   R₁₂ is a lower alkyl group or D;    -   D₁ is a hydrogen or D;    -   D is Q or K;    -   Q is —NO or —NO₂;    -   K is        —W_(a)—E_(b)—(C(R_(e))(R_(f)))_(p)-E_(c)-(C(R_(e))(R_(f)))_(y)—W_(d)—(C(R_(e))(R_(f)))_(y)—W_(i)-E_(j)-W_(g)—(C(R_(e))(R_(f)))_(z)-T-Q;    -   a, b, c, d, g, i and j are each independently an integer from 0        to 3;    -   p, x, y and z are each independently an integer from 0 to 10;    -   W at each occurrence is independently —C(O)—, —C(S)—, -T-,        —(C(R_(e))(R_(f)))_(h)—, an alkyl group, an aryl group, a        heterocyclic ring, an arylheterocyclic ring, or —(CH₂CH₂O)_(q)—;    -   E at each occurrence is independently -T-, an alkyl group, an        aryl group, —(C(R_(e))(R_(f)))_(h)—, a heterocyclic ring, an        arylheterocyclic ring, or —(CH₂CH₂O)_(q)—;    -   h is an integer form 1 to 10;    -   q is an integer from 1 to 5;    -   R_(e) and R_(f) are each independently a hydrogen, an alkyl, a        cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an        alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, a        cycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy,        an amino, an alkylamino, a dialkylamino, an arylamino, a        diarylamino, an alkylarylamino, an alkoxyhaloalkyl, a        haloalkoxy, a sulfonic acid, a sulfonic ester, an alkylsulfonic        acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an        arylthio, a cycloalkylthio, a cycloalkenyl, a cyano, an        aminoalkyl, an aminoaryl, an aryl, an arylalkyl, an alkylaryl, a        carboxamido, a alkylcarboxamido, an arylcarboxamido, an amidyl,        a carboxyl, a carbamoyl, an alkylcarboxylic acid, an        arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, an        ester, a carboxylic ester, an alkylcarboxylic ester, an        arylcarboxylic ester, a haloalkoxy, a sulfonamido, an        alkylsulfonamido, an arylsulfonamido, a sulfonic ester, a urea,        a phosphoryl, a nitro, -T-Q , or (C(R_(e))(R_(f)))_(k)-T-Q, or        R_(e) and R_(f) taken together with the carbon atoms to which        they are attached form a carbonyl, a methanthial, a heterocyclic        ring, a cycloalkyl group or a bridged cycloalkyl group;    -   k is an integer from 1 to 3;    -   T at each occurrence is independently a covalent bond, a        carbonyl, an oxygen, —S(O)_(O)— or —N(R_(a))R_(i)—;    -   o is an integer from 0 to 2;    -   R_(a) is a lone pair of electrons, a hydrogen or an alkyl group;    -   R_(i) is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid,        an arylcarboxylic acid, an alkylcarboxylic ester, an        arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido,        an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an        arylsulfinyl, an arylsulfonyl, a sulfonamido, a carboxamido, a        carboxylic ester, an amino alkyl, an amino aryl,        —CH₂—C(T-Q)(R_(e))(R_(f)), or —(N₂O₂—)⁻.M⁺, wherein M⁺ is an        organic or inorganic cation; with the proviso that when R_(i) is        —CH₂—C(T-Q)(R_(e))(R_(f)) or —(N₂O₂)-M⁺, or R_(e) or R_(f) are        T-Q or (C(R_(e))(R_(f)))_(k)-T-Q, then the “-T-Q” subgroup can        be a hydrogen, an alkyl, an alkoxy, an alkoxyalkyl, an        aminoalkyl, a hydroxy, a heterocyclic ring or an aryl group; and    -   with the proviso that the compounds of Formula (I) must contain        at least one nitrite, nitrate, thionitrite or thionitrate group.

In cases where R_(e) and R_(f) are a heterocyclic ring or taken togetherR_(e) and R_(f) are a heterocyclic ring, then R_(i) can be a substituenton any disubstituted nitrogen contained within the radical where R_(i)is as defined herein.

In cases where multiple designations of variables which reside insequence are chosen as a “covalent bond” or the integer chosen is 0, theintent is to denote a single covalent bond connecting one radical toanother. For example, E₀ would denote a covalent bond, while E₂ denotes(E-E) and (C(R_(e))(R_(f)))₂ denotes —C(R_(e))(R_(f))—C(R_(e))(R_(f))—.

Another embodiment of the present invention describes compounds ofFormula (II) or pharmaceutically acceptable salts thereof:

wherein

-   -   R₈ is a lower alkyl group, an alkoxyalkyl group, an alkylaryl        group, a cycloalkyl group, a cycloalkylalkyl group, an aryl        group, an alkylaryl group, or K;    -   R₉ at each occurrence is independently a hydrogen, a lower alkyl        group, an akylthio group, a halogen, a cyano group an alkanoyl        group, a haloalkyl group, a carbamoyl group, —NR₇D₁, —OD₁, or        —CO₂R₁₂;    -   R₇₁ is a hydrogen, a lower alkyl group, an alkoxy group, or        —OD₁;    -   J, K, D₁, R₇, R₁₂, q and o are as defined herein; and    -   with the proviso that the compounds of Formula (II) must contain        at least one nitrite, nitrate, thionitrite or thionitrate group.

Another embodiment of the present invention describes compounds ofFormula (I) or pharmaceutically acceptable salts thereof:

wherein

-   -   R₁₃ and R₁₄ are each independently a hydrogen a lower alkyl        group, an alkoxyalkyl, or a lower alkyl-OD₁; or R₁₃ and R₁₄        taken together along with the carbon atoms to which they are        attached form a cycloalkyl group or an aryl group;    -   R₁₇ is a hydrogen or a lower alkyl group;    -   Y₃ is:

wherein

-   -   R₁₅ is a hydrogen or a lower alkyl group;    -   R₁₆ is a hydrogen, a halogen, or a lower alkyl group;    -   R₆₃ is a lower alkyl group or a phenyl group;    -   A₁, A₂ and A₃ comprise the other subunits of a 5- or 6-membered        monocyclic aromatic ring and A₁, A₂ and A₃ are each        independently:        -   (i) CR_(o), wherein R_(o) at each occurrence is hydrogen or            —OD₁;        -   (ii) N—R_(p), wherein R_(p) at each occurrence is            independently a covalent bond to an adjacent ring atom in            order to render the ring aromatic, a hydrogen, or K;        -   (iii) a sulfur atom;        -   (iv) an oxygen atom; or        -   (v) B_(a)=B_(b), wherein B_(a) and B_(b) are each            independently a nitrogen atom or CR_(o);            -   wherein R_(o) at each occurrence is hydrogen or —OD₁;    -   D₁ and K are as defined herein; and    -   with the proviso that the compounds of Formula (III) must        contain at least one nitrite, nitrate, thionitrite or        thionitrate group.

Another embodiment of the present invention describes compounds ofFormula (IV) or pharmaceutically acceptable salts thereof:

wherein

-   -   R₁₈ and R₁₉ at each occurrence are each independently a        hydrogen, a lower alkyl group, a halogen, a nitro group, an        alkoxy group, —OD₁, —NR₂₀R₂₁, —O(O)CR₂₀, —O(O)COR₂₀,        —O(O)CNR₂₀R₂₁, —N(R₂₀)C(O)R₂₁, —N(R₂₀)C(O)NR₂₀R₂₁, or        —N(R₂₀)C(O)OR₂₁; or R₁₈ and R₁₉ when taken together along with        the carbon atoms to which they are attached form a heterocyclic        ring or a phenyl ring optionally substituted with up to four        substituents selected from a hydrogen, a lower alkyl group, a        halogen, a nitro group, an alkoxy group, —OD₁, —NR₂₀R₂₁,        —O(O)CR₂₀, —O(O)COR₂₀, —O(O)CNR₂₀R₂₁, —N(R₂₀)C(O)R₂₁,        —N(R₂₀)C(O)NR₂₀R₂₁, or —N(R₂₀)C(O)OR₂₁;    -   R₂₀ and R₂₁ at each occurrence are each independently a        hydrogen, a lower alkyl group, an aryl group, a lower alkylaryl        group, or K;    -   X₄ is —C(═R₆)R₂₂, a heterocyclic ring, —NR₂₀R₂₁, a halogen, an        alkoxy group, an arylalkoxy group, a cycloalkoxy group, a        heterocyclicalkoxy group, an alkylsulfonyl group, an        alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl        group an arylalkylsulfonyl group, an arylalkylsulfinyl group, a        heterocyclicsulfonyl group, or a heterocyclicsulfinyl group;    -   R₂₂ is a hydrogen, an alkyl group, an alkoxy group, an aryl        group, an alkylaryl group, a heterocyclic ring, an        —O-heterocyclic ring, or an alkylheterocyclic ring;    -   D₁, R₆, and K are defined as herein; and    -   with the proviso that the compounds of Formula (IV) must contain        at least one nitrite, nitrate, thionitrite or thionitrate group.

Another embodiment of the present invention describes compounds ofFormula (V) or pharmaceutically acceptable salt thereof:

wherein

-   -   X₅ is:

wherein

-   -   R₂₃ is a hydrogen, a dialkylamino group, —NR₇R₇′, or a        heterocyclic ring;    -   R₂₄ is a hydrogen or halogen;    -   R₂₅ is a hydrogen, —OD₁, or lower alkyl-OD₁;    -   R₂₇ at each occurrence is independently a hydrogen or an alkoxy        group;    -   R₂₈, R₂₉, and R₃₀ are each independently a hydrogen, a lower        alkyl group, a dialkylamino group, a heterocyclic ring, or a        lower alkyl-OD₁;    -   R₃₁ is a hydrogen, a dialkylamino group, or an alkoxy group;    -   R₃₃ is a hydrogen or a lower alkyl group;    -   n is an integer from 0 to 1;    -   R₇, R₇′, D₁ and q are as defined herein; and    -   with the proviso that the compounds of Formula (V) must contain        at least one nitrite, nitrate, thionitrite or thionitrate group.

Another embodiment of the present invention describes compounds ofFormula (VI) or pharmaceutically acceptable salts thereof:

wherein

-   -   A₄, A₅, and A₆ are each independently a sulfur or CR₃₄ with the        proviso that one of A₄, A₅, or A₆ is a sulfur and the other two        are CR₃₄;    -   R₃₄ at each occurrence is independently a hydrogen, a halogen, a        cyano, a nitro, a trifluoromethyl, a lower alkyl group, a        heterocyclic ring, a lower alkyl-OD₁, an alkoxy, a haloalkoxy,        an alkylthio, an alkylsulfinyl, an alkylsulfonyl, an        alkylcarbonyl, an alkoxycarbonyl, a carbamoyl, a        N-alkylcarbamoyl, a N,N-di-alkylcarbamoyl, an ester, a        cycloalkyl, an aryl, an alkylaryl, an aryloxy, an arylalkoxyoxy,        an arylamino, a alkylarylamino, an arylthio, an arylsulfonyl, an        arylsulfinyl, or a sulfonamido;    -   R₃₅ and R₃₆ are each independently a hydrogen or a lower alkyl        group; or R₃₅ and R₄₁ taken together with the carbon chain to        which they are attached form a cycloalkyl ring;    -   R₂₆ is:

wherein

-   -   X₆ is nitrogen, and Y₆ is CR₃₇; or X₆ is CR₃₇, and Y₆ is        nitrogen;    -   R₃₇ is a hydrogen, a halogen, a lower alkyl group, a        trifluoromethyl, an alkoxy group, a haloalkoxy group, an aryl        group, an arylalkoxy group, a heterocyclic ring, or an aryloxy;    -   Z₆ is —NR₃₈R₃₉, SR₄₀, or an arylalkoxy group;    -   R₃₈ and R₃₉ are each independently a hydrogen, a lower alkyl        group, an aryl group, an alkylaryl group, or a cycloalkyl group;        or R₃₈ and R₃₉ taken together with the nitrogen to which they        are attached form a heterocyclic ring;    -   R₄₀ is a hydrogen, a halogen, a lower alkyl group, an alkylaryl        group, an alkenyl group, or a haloalkyl group;    -   R₄₁, R₄₂, R₄₃, and R₄₄ are each independently a hydrogen, a        halogen, a lower alkyl group, an alkoxy group, a haloalkoxy        group, an alkoxyaryl group, an alkylthio group, an alkysulfinyl        group, an alkylsulfonyl group, a cyano group, —Y—OD₁, Y—SD₁,        —Y—NR₂₀R₂₁, —Y—O(O)CR₂₀, —Y—O(O)CNR₂₀R₂₁, —Y—N(R₂₀)C(O)R₂₁, or        —Y—N(R₂₀)S(O)₂R₂₁;    -   Y is —(CH₂)_(a)— or a phenyl group;    -   R₄₅ and R₄₆ are each independently a hydrogen, a lower alkyl        group, a cycloalkyl group, an alkenyl group, or an alkynyl        group;    -   D₁, R₂₀, R₂₁, and a are as defined herein; and    -   with the proviso that the compounds of Formula (VI) must contain        at least one nitrite, nitrate, thionitrite or thionitrate group.

Another embodiment of the present invention describes compounds ofFormula (VII) or pharmaceutically acceptable salts thereof:

wherein

-   -   R₆₀ is a lower alkyl group, an aryl group, a haloalkyl group, a        lower alkyl-OD₁, or heterocyclic ring;    -   A₇ is oxygen or —ND₁;    -   X₇ is a hydrogen or a halogen;    -   Y₇ is:

-   -   or X₇, A₇, and Y₇ taken together along with the carbons to which        they are attached is:

wherein

-   -   R₆₁ is a hydrogen, a halogen, a lower alkyl group, —OD₁, or        —NHC(O)O-lower alkyl;    -   R₆₂ is a hydrogen, a halogen, or a lower alkyl group; and    -   D₁ is as defined herein.

Compounds of the present invention that have one or more asymmetriccarbon atoms may exist as the optically pure enantiomers, purediastereomers, mixtures of enantiomers, mixtures of diastereomers,racemic mixtures of enantiomers, diastereomeric racemates or mixtures ofdiastereomeric racemates. It is to be understood that the presentinvention anticipates and includes within its scope all such isomers andmixtures thereof.

It is also to be understood that the present invention is intended toinclude within its scope compounds which may exist in more than oneresonance form and the effects that the resonance form may have on thepositions at D₁ substituents designated in the structures describedherein.

Another embodiment of the present invention provides processes formaking the novel compounds of the present invention and to theintermediates useful in such processes. The reactions are performed insolvents appropriate to the reagents and materials used are suitable forthe transformations being effected. It is understood by one skilled inthe art of organic synthesis that the functionality present in themolecule must be consistent with the chemical transformation proposed.This will, on occasion, necessitate judgment by the routineer as to theorder of synthetic steps, protecting groups required, and deprotectionconditions. Substituents on the starting materials may be incompatiblewith some of the reaction conditions required in some of the methodsdescribed, but alternative methods and substituents compatible with thereaction conditions will be readily apparent to skilled practitioners inthe art. The use of sulfur, oxygen and nitrogen protecting groups iswell known in the art for protecting thiol, alcohol, and amino groupsagainst undesirable reactions during a synthetic procedure and many suchprotecting groups are known and described by, for example, Greene andWuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley& Sons, New York (1999).

The chemical reactions described herein are generally disclosed in termsof their broadest application to the preparation of the compounds ofthis invention. Occasionally, the reactions may not be applicable asdescribed to each compound included within the disclosed scope. Thecompounds for which this occurs will be readily recognized by oneskilled in the art. In all such cases, either the reactions can besuccessfully performed by conventional modifications known to oneskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilyprepared from known starting materials.

The compounds of Formulas (I), (II), (III), (IV), (V), (VI) and (VII)can be synthesized by one skilled in the art following the methods andexamples described herein. The synthesis of the parent proton pumpinhibitors (i.e. non-nitrosated and non-nitrosylated proton pumpinhibitors) are disclosed in, for example, U.S. Pat. Nos. 4,045,564,4,255,431, 4,634,710, 4,758,579, 4,839,365, 4,873,337, 4,981,861,5,149,702, 5,554,631, 5,703,097 and 5,945,425 and in EP 0 045 200 A1, EP0 221 041 A2, EP 0 246 774 A1 and EP 0 254 588 A1 and in WO 98/54172 forthe compounds of Formula (I); and in U.S. Pat. Nos. 4,806,549, 4,806,550and 5,952,504 and in EP 0 259 174 A1 and in WO 89/08104 and WO 92/12969for the compounds of Formula (II); and in U.S. Pat. Nos. 5,686,458,5,750,531 and 5,990,311 and in WO 98/18784 and WO 98/43968 for thecompounds of Formula (III); and in U.S. Pat. No. 5,677,302 for thecompounds of Formula (IV); and in WO 97/32854 for the compounds ofFormula (V); and in U.S. Pat. Nos. 4,818,760, 4,845,118, 4,871,734,4,956,366 and 5,114,955 and in EP 0 234 485 A1 for the compounds ofFormula (VI); and in U.S. Pat. Nos. 5,439,917 and 5,665,730 and in EP 0033 094 B1 and in WO 95/27714 for the compounds of Formula (VII); thedisclosures of each of which are incorporated by reference herein intheir entirety.

The nitrosated and nitrosylated proton pump inhibitors of the presentinvention can be synthesized as shown in reaction Schemes 1 through 7presented herein. The parent proton pump inhibitor compounds can benitrosated and/or nitrosylated through one or more sites such as oxygen,sulfur, carbon and/or nitrogen using the methods described in theexamples herein and using conventional methods known to one skilled inthe art. For example, known methods for nitrosating and nitrosylatingcompounds are described in U.S. Pat. Nos. 5,380,758 and 5,703,073; WO97/27749; WO 98/19672; and Oae et al, Org. Prep. Proc. Int.,15(3):165-198 (1983), the disclosures of each of which are incorporatedby reference herein in their entirety. The methods of nitrosating and/ornitrosylating the compounds described in the examples herein and inthese references can be applied by one skilled in the art to produce anyof the nitrosated and/or nitrosylated proton pump inhibitors describedherein.

Nitroso or nitro compounds of formula (I), where X is a —ONO, —SNO, or—ONO₂ group and R₁, R₂, R₃, R₄, R₅, R₁₀, R₁₁, A, B, J, R_(e), R_(f), andp are as defined herein, and a nitrite, nitrate, or thionitritecontaining carbamate is representative of the D₁ group, as definedherein, may be prepared as shown in Scheme 1. The substituted imidazolenitrogen group of formula 1 is converted to the anion by treatment withone equivalent of a strong non-nucleophilic base, such as sodium hydrideor potasium hydride, in an aprotic solvent, such as tetrahydrofuran(THF) or dimethylformamide (DMF). The carbamate of formula IA, IB, or ICwhere p, X, R_(e) and R_(f) are as defined herein, is prepared byreacting the imidazole anion with a suitably functionalizedchloroformate in an inert solvent, such as THF or DMF. Typically thecoupling reaction is performed at a temperature ranging from −78° C. toroom temperature. Preferred methods for the formation of chloroformatesare reacting one equivalent of a X functionalized alcohol with oneequivalent of phosgene at a temperature ranging from −78° C. to 0° C. inan inert solvent, such as ether or THF and in the presence of an aminebase, such as pyridine or triethylamine. Removal of the aminehydrochloride by filtration affords a solution of the desiredchloroformate which may be used directly or concentrated and redissolvedin the anhydrous solution of choice prior to the coupling reaction withthe imidazole anion to afford the carbamate of formula IA, IB, or IC.

On occasion it might be desirable to nitrosylate the alcohol or thiolafter coupling a chloroformate to the imidazole anion. The chloroformatewould be prepared by reacting phosgene with an alcohol containing aprotected alcohol or thiol moiety. Preferred protecting groups for analcohol moiety are silyl ethers, such as a trimethylsilyl ether, atert-butyldimethylsilyl ether, or a tert-butyldiphenylsilyl ether. Afterformation of the carbamate, deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction with a suitable nitrosylatingagent, such as thionyl chloride nitrite, thionyl dinitrite, ornitrosonium tetrafluoroborate, in a suitable anhydrous solvent, such asdichloromethane, THF, DMF, or acetonitrile, with or without an aminebase, such as pyridine or triethylamine affords the compound of formulaIA. Preferred protecting groups for the thiol moiety are as a thioester,such as a thioacetate or a thiobenzoate or as a disulfide. Deprotectionof the thiol moiety (zinc in dilute aqueous acid, triphenylphosphine inwater and sodium borohydride are preferred methods for reducingdisulfide groups while aqueous base or sodium methoxide in methanol istypically used to hydrolyze thioesters) followed by reaction with asuitable nitrosylating agent such, as thionyl chloride nitrite, thionyldinitrite, a lower alkyl nitrite, such as tert-butyl nitrite, ornitrosonium tetrafluoroborate, in a suitable anhydrous solvent, such asmethylene chloride, THF, DMF, or acetonitrile, with or without an aminebase, such as pyridine or triethylamine, affords the compound of formulaIB. Nitrosation of the carbamate product may be accomplished by firstconverting the deprotected alcohol to a leaving group such as a mesylateor a tosylate. This reaction is typically performed at a temperature of0° C. to room temperature in an inert solvent, such as ether, THF, ordichloromethane with the alcohol, methansulfonyl chloride orpara-toluensulfonyl chloride, and an amine base, such as triethylamineor pyridine, as the reactants. The corresponding iodide is then preparedby reacting the mesylate or tosylate with sodium iodide in acetone. Thehalide may also be formed from the alcohol by treatment of the hydroxylmoiety with a phosphorus reagent, such as triphenylphosphine, in thepresence of a halide source, such as carbon tetrabromide orN-iodosuccimide, in an inert solvent, such as THF. Treatment of thebromide or iodide with silver nitrate in an inert solvent, such asacetonitrile, affords the compound of formula IC. Alternatively, thehalide containing carbamate may be formed directly by preparing a halidecontaining chloroformate from a halide containing alcohol. Preferredhalides are bromide and iodide. Coupling of the imidazole anion with thehalide containing chloroformate followed by reaction of the carbamateproduct with silver nitrate in an inert solvent, such as acetonitrile,affords the compound of formula IC.

Nitroso or nitro compounds of formula (II), where X is a —ONO, —SNO, or—ONO₂ group and R₈, R₉, R₇₁, D₁, J, R_(e), R_(f), o, p, and q are asdefined herein, and a nitrite, nitrate, or thionitrite containingalkoxyethyl ester is representative of the K group, as defined herein,may be prepared as shown in Scheme 2. The hydroxyl group of formula 2 isconverted to the ester of formula IIA, IIB, or IIC, where p, R_(e),R_(f) and X are as defined herein, by reaction with an appropriatenitrite, thionitrite, or nitrate containing activated acylating agent.Preferred methods for the formation of esters are reacting the alcoholwith the preformed acid chloride or anhydride of the nitrite,thionitrite, or nitrate containing acid. Preferred methods for preparingacid chlorides are treating the carboxylic acid with oxalyl chloride anda catalytic amount of DMF in an inert solvent, such as ether, THF,dichloromethane, or toluene. Preferred methods for preparing mixedanhydride are reacting the carboxylic acid with a chloroformate such asisobutylchloroformate in the presence of an amine base, such astriethylamine in an inert solvent, such as ether, THF, dichloromethane,or toluene. Alternatively, the alcohol and nitrite, thionitrite, ornitrate containing acid may be condensed in the presence of adehydrating agent, such as dicyclohexylcarbodimide (DCC) or 1-ethyl-3(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC.HCl) with orwithout a catalyst, such as 4-dimethylaminopyridine (DMAP) or1-hydroxybenzotriazole (HOBt).

On occasion it might be desirable to nitrosylate the alcohol or thiolafter coupling the activated acylating agent to the alcohol. Theactivated acylating agent would be prepared from an acid containing aprotected alcohol or thiol moiety. Preferred protecting groups for analcohol moiety are silyl ethers, such as a trimethylsilyl ether, atert-butyldimethylsilyl ether, or a tert-butyldiphenylsilyl ether. Afterformation of the ester, deprotection of the hydroxyl moiety (fluorideion is the preferred method for removing silyl ether protecting groups)followed by reaction with a suitable nitrosylating agent, such asthionyl chloride nitrite, thionyl dinitrite, or nitrosoniumtetrafluoroborate, in a suitable anhydrous solvent, such asdichloromethane, THF, DMF, or acetonitrile, with or without an aminebase, such as pyridine or triethylamine, affords the compound of formulaIIA. Preferred protecting groups for the thiol moiety are as athioester, such as a thioacetate or a thiobenzoate, or as a disulfide.Deprotection of the thiol moiety (zinc in dilute aqueous acid,triphenylphosphine in water and sodium borohydride are preferred methodsfor reducing disulfide groups while aqueous base or sodium methoxide inmethanol is typically used to hydrolyze thioesters) followed by reactionwith a suitable nitrosylating agent such, as thionyl chloride nitrite orthionyl dinitrite, a lower alkyl nitrite, such as tert-butyl nitrite, ornitrosonium tetrafluoroborate, in a suitable anhydrous solvent, such asmethylene chloride, THF, DMF, or acetonitrile, with or without an aminebase, such as pyridine or triethylamine, affords the compound of formulaIIB. Nitrosation of the ester product may be accomplished by firstconverting the deprotected alcohol to a leaving group, such as amesylate or a tosylate. This reaction is typically performed at atemperature of 0° C. to room temperature in an inert solvent, such asether, THF, or dichloromethane with the alcohol, methansulfonyl chlorideor para-toluensulfonyl chloride, and an amine base, such astriethylamine or pyridine, as the reactants. The corresponding iodide isthen prepared by reacting the mesylate or tosylate with sodium iodide inacetone. The halide may also be formed from the alcohol by treatment ofthe hydroxyl moiety with a phosphorus reagent, such astriphenylphosphine, in the presence of a halide source, such as carbontetrabromide or N-iodosuccimide, in an inert solvent, such as THF.Treatment of the bromide or iodide with silver nitrate in an inertsolvent, such as acetonitrile affords the compound of formula IIC.Alternatively, the halide containing ester may be formed directly bypreparing a halide containing active acylating agent from a halidecontaining acid. Preferred halides are bromide and iodide. Coupling ofthe alcohol with the halide containing active acylating agent followedby reaction of the ester product with silver nitrate in an inertsolvent, such as acetonitrile affords the compound of formula IIC.Preferred coupling methods for the formation of esters from alcohols arethose methods described herein (e.g. with the preformed acid chloride oranhydride or with the carboxylic acid and a dehydration agent, such asDCC or EDAC.HCl).

Nitroso or nitro compounds of formula (III), where X is a —ONO, —SNO, or—ONO₂ group and R₁₄, R₁₇, A₁, A₂, A₃, R_(e), R_(f), Y₃, and p, are asdefined herein, and a nitrite, nitrate, or thionitrite containingacyloxymethyl ester is representative of the R₁₃ group may be preparedas shown in Scheme 3. The hydroxyl group of formula 3 is converted tothe ester of formula IIIA, IIIB, or IIIC, where p, R_(e), R_(f) and Xare as defined herein, by reaction with an appropriate nitrite,thionitrite, or nitrate containing activated acylating agent. Preferredmethods for the formation of esters are reacting the alcohol with thepreformed acid chloride or symmetrical anhydride of the nitrite,thionitrite, or nitrate containing acid. Preferred methods for preparingacid chlorides are treating the carboxylic acid with oxalyl chloride anda catalytic amount of DMF in an inert solvent, such as ether, THF,dichloromethane, or toluene. Preferred methods for preparing mixedanhydride are reacting the carboxylic acid with a chloroformate, such asisubutylchloroformate, in the presence of an amine base, such astriethylamine in an inert solvent solvent, such as ether, THF,dichloromethane, or toluene. Alternatively, the alcohol and nitrite,thionitrite, or nitrate containing acid may be condensed in the presenceof a dehydrating agent, such as DCC or EDAC.HCl with or without acatalyst, such as DMAP or HOBt.

On occasion it might be desirable to nitrosylate the alcohol or thiolafter coupling the activated acylating agent to the alcohol. Theactivated acylating agent would be prepared from an acid containing aprotected alcohol or thiol moiety. Preferred protecting groups for analcohol moiety are silyl ethers, such as a trimethylsilyl ether, atert-butyldimethylsilyl ether, or a tert-butyldiphenylsilyl ether. Afterformation of the ester, deprotection of the hydroxyl moiety (fluorideion is the preferred method for removing silyl ether protecting groups)followed by reaction with a suitable nitrosylating agent, such asthionyl chloride nitrite, thionyl dinitrite, or nitrosoniumtetrafluoroborate, in a suitable anhydrous solvent, such asdichloromethane, THF, DMF, or acetonitrile, with or without an aminebase, such as pyridine or triethylamine affords the compound of formulaIIIA. Preferred protecting groups for the thiol moiety are as athioester, such as a thioacetate or a thiobenzoate or as a disulfide.Deprotection of the thiol moiety (zinc in dilute aqueous acid,triphenylphosphine in water and sodium borohydride are preferred methodsfor reducing disulfide groups while aqueous base or sodium methoxide inmethanol is typically used to hydrolyze thioesters) followed by reactionwith a suitable nitrosylating agent such, as thionyl chloride nitrite orthionyl dinitrite, a lower alkyl nitrite, such as tert-butyl nitrite, ornitrosonium tetrafluoroborate, in a suitable anhydrous solvent, such asmethylene chloride, THF, DMF, or acetonitrile, with or without an aminebase, such as pyridine or triethylamine, affords the compound of formulaIIIB. Nitrosation of the ester product may be accomplished by firstconverting the deprotected alcohol to a leaving group, such as amesylate or a tosylate. This reaction is typically performed at atemperature of 0° C. to room temperature in an inert solvent, such asether, THF, or dichloromethane with the alcohol, methansulfonyl chlorideor para-toluensulfonyl chloride, and an amine base, such astriethylamine or pyridine as the reactants. The corresponding iodide isthen prepared by reacting the mesylate or tosylate with sodium iodide inacetone. The halide may also be formed from the alcohol by treatment ofthe hydroxyl moiety with a phosphorus reagent, such astriphenylphosphine, in the presence of a halide source, such as carbontetrabromide or N-iodosuccimide, in an inert solvent, such as THF.Treatment of the bromide or iodide with silver nitrate in an inertsolvent, such as acetonitrile, affords the compound of formula IIIC.Alternatively, the halide containing ester may be formed directly bypreparing a halide containing active acylating agent from a halidecontaining acid. Preferred halides are bromide and iodide. Coupling ofthe alcohol with the halide containing active acylating agent followedby reaction of the ester product with silver nitrate in an inertsolvent, such as acetonitrile, affords the compound of formula IIIC.Preferred coupling methods for the formation of esters from alcohols arethose methods described herein (e.g. with the preformed acid chloride oranhydride or with the carboxylic acid and a dehydration agent, such asDCC or EDAC.HCl).

Nitroso or nitro compounds of formula (IV), where X is a —ONO, —SNO, or—ONO₂ group and R₁₈, R₁₉, R_(e), R_(f), and p, are as defined herein,and a nitrite, nitrate, or thionitrite containing carboxylic acid esteris representative of the X₄ group may be prepared as shown in Scheme 4.The acid of the formula 4 is converted to the ester of formula IVA, IVB,or IVC, where p, R_(e), R_(f) and X are as defined herein, by reactionwith an appropriate nitrite, thionitrite, or nitrate containing alcohol.Preferred methods for the preparation of esters are initially formingthe mixed anhydride via reaction of 4 with a chloroformate, such asisobutylchloroformate, in the presence of a non nucleophilic base, suchas triethylamine, in an anhydrous inert solvent, such asdichloromethane, diethylether or THF. The mixed anhydride is thenreacted with the nitrite, thionitrite, or nitrate containing alcoholpreferably in the presence of a condensation catalyst, such as DMAP.Alternatively, the acid 4 may be first converted to the acid chloride bytreatment with oxalyl chloride in the presence of a catalytic amount ofDMF. The acid chloride is then reacted with the nitrite, thionitrite, ornitrate containing alcohol preferably in the presence of a condensationcatalyst, such as DMAP, and a tertiary amine base, such astriethylamine, to afford the ester of formula IVA, IVB, or IVC.Alternatively, the acid 4 and nitrite, thionitrite, or nitratecontaining alcohol may be coupled to afford the ester of formula IVA,IVB, or IVC by treatment with a dehydration agent, such as DCC orEDAC.HCl, with or without a catalyst, such as DMAP or HOBt.

On occasion it might be desirable to nitrosylate the alcohol or thiolafter coupling the acid to the alcohol. The ester would be prepared byreacting the carboxylic acid with an alcohol containing a protectedalcohol or thiol moiety. Preferred protecting groups for an alcoholmoiety are silyl ethers, such as a trimethylsilyl ether, atert-butyldimethylsilyl ether, or a tert-butyldiphenylsilyl ether. Aftercoupling the acid and alcohol moieties, deprotection of the hydroxylmoiety (fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction with a suitable nitrosylatingagent, such as thionyl chloride nitrite, thionyl dinitrite, ornitrosonium tetrafluoroborate, in a suitable anhydrous solvent, such asdichloromethane, THF, DMF, or acetonitrile, with or without an aminebase, such as pyridine or triethylamine, affords the compound of formulaIVA. Preferred protecting groups for the thiol moiety are as athioester, such as a thioacetate or a thiobenzoate or as a disulfide.Deprotection of the thiol moiety (zinc in dilute aqueous acid,triphenylphosphine in water and sodium borohydride are preferred methodsfor reducing disulfide groups while aqueous base or sodium methoxide inmethanol is typically used to hydrolyze thioesters) followed by reactionwith a suitable nitrosylating agent such, as thionyl chloride nitrite,thionyl dinitrite, a lower alkyl nitrite, such as tert-butyl nitrite, ornitrosonium tetrafluoroborate, in a suitable anhydrous solvent, such asmethylene chloride, THF, DMF, or acetonitrile, with or without an aminebase, such as pyridine or triethylamine, affords the compound of formulaIVB. Nitrosation of the ester product containing a deprotected alcoholmoiety may be accomplished by first converting the alcohol to a leavinggroup, such as a mesylate or a tosylate. This reaction is typicallyperformed at a temperature of 0° C. to room temperature in an inertsolvent, such as ether, THF, or dichloromethane with the alcohol,methansulfonyl chloride or para-toluensulfonyl chloride, and an aminebase, such as triethylamine or pyridine, as the reactants. Thecorresponding iodide is then prepared by reacting the mesylate ortosylate with sodium iodide in acetone. The halide may also be formedfrom the alcohol by treatment of the hydroxyl moiety with a phosphorusreagent, such as triphenylphosphine, in the presence of a halide source,such as carbon tetrabromide or N-iodosuccimide, in an inert solvent,such as THF. Treatment of the bromide or iodide with silver nitrate inan inert solvent, such as acetonitrile, affords the compound of formulaIVC. Alternatively, the halide containing ester may be formed directlyby preparing a halide containing active acylating agent from a halidecontaining acid. Preferred halides are bromide and iodide. Coupling ofthe alcohol with the halide containing active acylating agent followedby reaction of the ester product with silver nitrate affords thecompound of formula IVC. Preferred coupling methods for the formation ofesters from alcohols are those methods described herein (e.g. with thepreformed acid chloride or anhydride or with the carboxylic acid and adehydration agent, such as DCC or EDAC.HCl).

Nitroso or nitro compounds of formula (V), where X is a —ONO, —SNO, or—ONO₂ group and R₂₃, R₂₄, R₂₅, R₂₇, R₂₉, R₃₀, R_(e), R_(f), n and p, areas defined herein, and nitrate, or thionitrite containing ester of asubstituted pyridine is representative of the X₅ group may be preparedas shown in Scheme 5. The hydroxyl group of formula 5 is converted tothe ester of formula VA, VB, or VC, where p, R_(e), R_(f) and X are asdefined herein, by reaction with an appropriate nitrite, thionitrite, ornitrate containing activated acylating agent. Preferred methods for theformation of esters are reacting the alcohol with the preformed acidchloride or symmetrical anhydride of the nitrite, thionitrite, ornitrate containing acid. Preferred methods for preparing acid chloridesare treating the carboxylic acid with oxalyl chloride and a catalyticamount of DMF in an inert solvent, such as ether, THF, dichloromethane,or toluene. Preferred methods for preparing mixed anhydride are reactingthe carboxylic acid with a chloroformate, such as isubutylchloroformate,in the presence of an amine base, such as triethylamine, in an inertsolvent solvent, such as ether, THF, dichloromethane, or toluene.Alternatively, the alcohol and nitrite, thionitrite, or nitratecontaining acid may be condensed in the presence of a dehydrating agent,such as DCC or EDAC.HCl, with or without a catalyst, such as DMAP orHOBt.

On occasion it might be desirable to nitrosylate the alcohol or thiolafter coupling the activated acylating agent to the alcohol. Theactivated acylating agent would be prepared from an acid containing aprotected alcohol or thiol moiety. Preferred protecting groups for analcohol moiety are silyl ethers, such as a trimethylsilyl ether, atert-butyldimethylsilyl ether, or a tert-butyldiphenylsilyl ether. Afterformation of the ester, deprotection of the hydroxyl moiety (fluorideion is the preferred method for removing silyl ether protecting groups)followed by reaction with a suitable nitrosylating agent, such asthionyl chloride nitrite, thionyl dinitrite, or nitrosoniumtetrafluoroborate, in a suitable anhydrous solvent, such asdichloromethane, THF, DMF, or acetonitrile, with or without an aminebase, such as pyridine or triethylamine affords the compound of formulaVA. Preferred protecting groups for the thiol moiety are as a thioester,such as a thioacetate or a thiobenzoate or as a disulfide. Deprotectionof the thiol moiety (zinc in dilute aqueous acid, triphenylphosphine inwater and sodium borohydride are preferred methods for reducingdisulfide groups while aqueous base or sodium methoxide in methanol istypically used to hydrolyze thioesters) followed by reaction with asuitable nitrosylating agent, such as thionyl chloride nitrite, thionyldinitrite, a lower alkyl nitrite, such as tert-butyl nitrite, ornitrosonium tetrafluoroborate, in a suitable anhydrous solvent, such asmethylene chloride, THF, DMF, or acetonitrile, with or without an aminebase, such as pyridine or triethylamine, affords the compound of formulaVB. Nitrosation of the ester product may be accomplished by firstconverting the deprotected alcohol to a leaving group, such as amesylate or a tosylate. This reaction is typically performed at atemperature of 0° C. to room temperature in an inert solvent, such asether, THF, or dichloromethane with the alcohol, methansulfonyl chlorideor para-toluensulfonyl chloride, and an amine base, such astriethylamine or pyridine as the reactants. The corresponding iodide isthen prepared by reacting the mesylate or tosylate with sodium iodide inacetone. The halide may also be formed from the alcohol by treatment ofthe hydroxyl moiety with a phosphorus reagent, such astriphenylphosphine in the presence of a halide source, such as carbontetrabromide or N-iodosuccimide in an inert solvent, such as THF.Treatment of the bromide or iodide with silver nitrate in an inertsolvent, such as acetonitrile, affords the compound of formula VC.Alternatively, the halide containing ester may be formed directly bypreparing a halide containing active acylating agent from a halidecontaining acid. Preferred halides are bromide and iodide. Coupling ofthe alcohol with the halide containing active acylating agent followedby reaction of the ester product with silver nitrate in an inertsolvent, such as acetonitrile, affords the compound of formula VC.Preferred coupling methods for the formation of esters from alcohols arethose methods described herein (e.g. with the preformed acid chloride oranhydride or with the carboxylic acid and a dehydration agent, such asDCC or EDAC.HCl).

Nitroso or nitro compounds of formula (VI), where X is a —ONO, —SNO, or—ONO₂ group and R₂₆, R₃₅, R₃₆, A, A₄, A₅, A₆, R_(e), R_(f), and p are asdefined herein, and a nitrite, nitrate, or thionitrite containingcarbamate is representative of the D₁ group, as defined herein, may beprepared as shown in Scheme 6. The substituted imidazole nitrogen groupof formula 6 is converted to the anion by treatment with one equivalentof a strong non-nucleophilic base, such as sodium hydride or potasiumhydride in an aprotic solvent, such as THF or DMF. The carbamate offormula VIA, VIB, or VIC where p, X, R_(e) and R_(f) are as definedherein, is prepared by reacting the imidazole anion with a suitablyfunctionalized chloroformate in an inert solvent, such as THF or DMF.Typically the coupling reaction is performed at a temperature rangingbetween −78° C. and room temperature. Preferred methods for theformation of cloroformates are reacting one equivalent of Xfunctionalized alcohol with one equivalent of phosgene at a tempeatureranging from −78° C. to 0° C. in an inert solvent, such as ether or THF,and in the presence of an amine base, such as pyridine or triethylamine.Removal of the amine hydrochloride by filtration affords a solution ofthe desired chloroformate which may be used directly or concentrated andredissolved in the anhydrous solution of choice prior to the couplingreaction with the imidazole anion to afford the carbamate of the formulaVIA, VIB, or VIC.

On occasion it might be desirable to nitrosylate the alcohol or thiolafter coupling a chloroformate to the imidazole anion. The chloroformatewould be prepared by reacting phosgene with an alcohol containing aprotected alcohol or thiol moiety. Preferred protecting groups for analcohol moiety are silyl ethers, such as a trimethylsilyl ether, atert-butyldimethylsilyl ether, or a tert-butyldiphenylsilyl ether. Afterformation of the carbamate, deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction with a suitable nitrosylatingagent, such as thionyl chloride nitrite, thionyl dinitrite, ornitrosonium tetrafluoroborate, in a suitable anhydrous solvent, such asdichloromethane, THF, DMF, or acetonitrile, with or without an aminebase, such as pyridine or triethylamine, affords the compound of formulaVIA. Preferred protecting groups for the thiol moiety are as athioester, such as a thioacetate or a thiobenzoate or as a disulfide.Deprotection of the thiol moiety (zinc in dilute aqueous acid,triphenylphosphine in water and sodium borohydride are preferred methodsfor reducing disulfide groups while aqueous base or sodium methoxide inmethanol is typically used to hydrolyze thioesters) followed by reactionwith a suitable nitrosylating agent, such as thionyl chloride nitrite,thionyl dinitrite, a lower alkyl nitrite, such as tert-butyl nitrite, ornitrosonium tetrafluoroborate, in a suitable anhydrous solvent, such asmethylene chloride, THF, DMF, or acetonitrile, with or without an aminebase, such as pyridine or triethylamine, affords the compound of formulaVIB. Nitrosation of the carbamate product may be accomplished by firstconverting the deprotected alcohol to a leaving group, such as amesylate or a tosylate. This reaction is typically performed at atemperature of 0° C. to room temperature in an inert solvent, such asether, THF, or dichloromethane, with the alcohol, methansulfonylchloride or para-toluensulfonyl chloride, and an amine base, such astriethylamine or pyridine, as the reactants. The corresponding iodide isthen prepared by reacting the mesylate or tosylate with sodium iodide inacetone. The halide may also be formed from the alcohol by treatment ofthe hydroxyl moiety with a phosphorus reagent, such astriphenylphosphine, in the presence of a halide source, such as carbontetrabromide or N-iodosuccimide, in an inert solvent, such as THF.Treatment of the bromide or iodide with silver nitrate in an inertsolvent such as acetonitrile affords the compound of formula VIC.Alternatively, the halide containing carbamate may be formed directly bypreparing a halide containing chloroformate from a halide containingalcohol. Preferred halides are bromide and iodide. Coupling of theimidazole anion with the halide containing chloroformate followed byreaction of the carbamate product with silver nitrate in an inertsolvent such as acetonitrile affords the compound of formula VIC.

Nitroso or nitro compounds of formula (VII), where X is a —ONO, —SNO, or—ONO₂ group and R₆₀, A₇, X₇, Y₇, R_(e), R_(f), and p, are as definedherein, and a nitrite, nitrate, or thionitrite containing acyl group isrepresentative of the D group may be prepared as shown in Scheme 7. Thehydroxyl group of formula 7 is converted to the ester of formula VIIA,VIIB, or VIIC, where p, R_(e) R_(f) and X are as defined herein, byreaction with an appropriate nitrite, thionitrite, or nitrate containingactivated acylating agent. Preferred methods for the formation of estersare reacting the alcohol with the preformed acid chloride or symmetricalanhydride of the nitrite, thionitrite, or nitrate containing acid.Preferred methods for preparing acid chlorides are treating thecarboxylic acid with oxalyl chloride and a catalytic amount of DMF in aninert solvent, such as ether, THF, dichloromethane, or toluene.Preferred methods for preparing mixed anhydride are reacting thecarboxylic acid with a chloroformate, such as isubutylchloroformate, inthe presence of an amine base, such as triethylamine, in an inertsolvent solvent, such as ether, THF, dichloromethane, or toluene.Alternatively, the alcohol and nitrite, thionitrite, or nitratecontaining acid may be condensed in the presence of a dehydrating agent,such as DCC or EDAC.HCl with or without a catalyst, such as DMAP orHOBt.

On occasion it might be desirable to nitrosylate the alcohol or thiolafter coupling the activated acylating agent to the alcohol. Theactivated acylating agent would be prepared from an acid containing aprotected alcohol or thiol moiety. Preferred protecting groups for analcohol moiety are silyl ethers, such as a trimethylsilyl ether, atert-butyldimethylsilyl ether, or a tert-butyldiphenylsilyl ether. Afterformation of the ester, deprotection of the hydroxyl moiety (fluorideion is the preferred method for removing silyl ether protecting groups)followed by reaction with a suitable nitrosylating agent, such asthionyl chloride nitrite, thionyl dinitrite, or nitrosoniumtetrafluoroborate, in a suitable anhydrous solvent, such asdichloromethane, THF, DMF, or acetonitrile, with or without an aminebase, such as pyridine or triethylamine affords the compound of formulaVIIA. Preferred protecting groups for the thiol moiety are as athioester, such as a thioacetate or a thiobenzoate or as a disulfide.Deprotection of the thiol moiety (zinc in dilute aqueous acid,triphenylphosphine in water and sodium borohydride are preferred methodsfor reducing disulfide groups while aqueous base or sodium methoxide inmethanol is typically used to hydrolyze thioesters) followed by reactionwith a suitable nitrosylating agent, such as thionyl chloride nitrite,thionyl dinitrite, a lower alkyl nitrite, such as tert-butyl nitrite, ornitrosonium tetrafluoroborate, in a suitable anhydrous solvent, such asmethylene chloride, THF, DMF, or acetonitrile, with or without an aminebase, such as pyridine or triethylamine, affords the compound of formulaVIIB. Nitrosation of the ester product may be accomplished by firstconverting the deprotected alcohol to a leaving group, such as amesylate or a tosylate. This reaction is typically performed at atemperature of 0° C. to room temperature in an inert solvent, such asether, THF, or dichloromethane with the alcohol, methansulfonyl chlorideor para-toluensulfonyl chloride, and an amine base, such astriethylamine or pyridine as the reactants. The corresponding iodide isthen prepared by reacting the mesylate or tosylate with sodium iodide inacetone. The halide may also be formed from the alcohol by treatment ofthe hydroxyl moiety with a phosphorus reagent, such astriphenylphosphine in the presence of a halide source, such as carbontetrabromide or N-iodosuccimide in an inert solvent, such as THF.Treatment of the bromide or iodide with silver nitrate in an inertsolvent, such as acetonitrile, affords the compound of formula VIIC.Alternatively, the halide containing ester may be formed directly bypreparing a halide containing active acylating agent from a halidecontaining acid. Preferred halides are bromide and iodide. Coupling ofthe alcohol with the halide containing active acylating agent followedby reaction of the ester product with silver nitrate in an inertsolvent, such as acetonitrile, affords the compound of formula VIIC.Preferred coupling methods for the formation of esters from alcohols arethose methods described herein (e.g. with the preformed acid chloride oranhydride or with the carboxylic acid and a dehydration agent, such asDCC or EDAC.HCl).

The compounds of the present invention include proton pump inhibitors,such as those described herein, which have been nitrosated and/ornitrosylated through one or more sites such as oxygen (hydroxylcondensation), sulfur (sulfhydryl condensation), carbon and/or nitrogen.The nitrosated and/or nitrosylated proton pump inhibitors of the presentinvention are capable of donating, transfering and/or releasing abiologically active form of nitrogen monoxide (i.e., nitric oxide).

Nitrogen monoxide can exist in three forms: NO-(nitroxyl), NO.(unchargednitric oxide) and NO⁺(nitrosonium). NO. is a highly reactive short-livedspecies that is potentially toxic to cells. This is critical because thepharmacological efficacy of NO depends upon the form in which it isdelivered. In contrast to the nitric oxide radical (NO.), nitrosonium(NO⁺) does not react with O₂ or O₂ ⁻ species, and functionalitiescapable of transferring and/or releasing NO⁺ and NO— are also resistantto decomposition in the presence of many redox metals. Consequently,administration of charged NO equivalents (positive and/or negative) is amore effective means of delivering a biologically active NO to thedesired site of action.

Compounds contemplated for use in the present invention (e.g., protonpump inhibitors optionally substituted with one or more NO and/or NO₂groups) can be used in combination with nitric oxide and compounds thatrelease nitric oxide (i.e., compounds that release nitric oxide orotherwise directly or indirectly deliver or transfer nitric oxide to asite of its activity, such as on a cell membrane, in vivo, and/orelevate or stimulate production of endogenous nitric oxide or EDRF invivo and/or is a substrate for nitric oxide synthase). “In combination,”as used herein can mean that (i) the proton pump inhibitor, optionallysubstituted with at least one NO and/or NO₂ group, and nitric oxidedonor can be present together in the same composition; (ii) the protonpump inhibitor, optionally substituted with at least one NO and/or NO₂group, and nitric oxide donor can be administered separately; and/or(iii) the proton pump inhibitor, optionally substituted with at leastone NO and/or NO₂ group, and nitric oxide donor can be together in theform of a kit.

The term “nitric oxide” encompasses uncharged nitric oxide (NO.) andcharged nitrogen monoxide species, preferably charged nitrogen monoxidespecies, such as nitrosonium ion (NO⁺) and nitroxyl ion (NO—). Thereactive form of nitric oxide can be provided by gaseous nitric oxide.The nitrogen monoxide releasing, delivering or transferring compoundshave the structure F—NO, wherein F is a nitrogen monoxide releasing,delivering or transferring moiety, and include any and all suchcompounds which provide nitrogen monoxide to its intended site of actionin a form active for its intended purpose. The term “NO adducts”encompasses any nitrogen monoxide releasing, delivering or transferringcompounds, including, for example, S-nitrosothiols, nitrites, nitrates,S-nitrothiols, sydnonimines, 2-hydroxy-2-nitrosohydrazines (NONOates),(E)-alkyl-2-[(E)-hydroxyimino]-5-nitro-3-hexene amines or amides,nitrosoamines, furoxans as well as substrates for the endogenous enzymeswhich synthesize nitric oxide. The “NO adducts” can bemono-nitrosylated, poly-nitrosylated, mono-nitrosated and/orpoly-nitrosated or a combination thereof at a variety of naturallysusceptible or artificially provided binding sites for biologicallyactive forms of nitrogen monoxide.

One group of NO adducts is the S-nitrosothiols, which are compounds thatinclude at least one —S—NO group. These compounds includeS-nitroso-polypeptides (the term “polypeptide” includes proteins andpolyamino acids that do not possess an ascertained biological function,and derivatives thereof); S-nitrosylated amino acids (including naturaland synthetic amino acids and their stereoisomers and racemic mixturesand derivatives thereof); S-nitrosylated sugars; S-nitrosylated,modified and unmodified, oligonucleotides (preferably of at least 5, andmore preferably 5-200 nucleotides); straight or branched, saturated orunsaturated, aliphatic or aromatic, substituted or unsubstitutedS-nitrosylated hydrocarbons; and S-nitroso heterocyclic compounds.S-nitrosothiols and methods for preparing them are described in U.S.Pat. Nos. 5,380,758 and 5,703,073; WO 97/27749; WO 98/19672; and Oae etal, Org. Prep. Proc. Int., 15(3): 165-198 (1983), the disclosures ofeach of which are incorporated by reference herein in their entirety.

Another embodiment of the present invention is S-nitroso amino acidswhere the nitroso group is linked to a sulfur group of asulfur-containing amino acid or derivative thereof. Such compoundsinclude, for example, S-nitroso-N-acetylcysteine, S-nitroso-captopril,S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine,S-nitroso-cysteine and S-nitroso-glutathione.

Suitable S-nitrosylated proteins include thiol-containing proteins(where the NO group is attached to one or more sulfur groups on an aminoacid or amino acid derivative thereof) from various functional classesincluding enzymes, such as tissue-type plasminogen activator (TPA) andcathepsin B; transport proteins, such as lipoproteins; heme proteins,such as hemoglobin and serum albumin; and biologically protectiveproteins, such as immunoglobulins, antibodies and cytokines. Suchnitrosylated proteins are described in WO 93/09806, the disclosure ofwhich is incorporated by reference herein in its entirety. Examplesinclude polynitrosylated albumin where one or more thiol or othernucleophilic centers in the protein are modified.

Other examples of suitable S-nitrosothiols include:

-   -   (i) HS(C(R_(e))(R_(f)))_(m)SNO;    -   (ii) ONS(C(R_(e))(R_(f)))_(m)R_(e); and    -   (iii) H₂N—CH(CO₂H)—(CH₂)_(m)—C(O)NH—CH(CH₂SNO)—C(O)NH—CH₂—CO₂H;        wherein m is an integer from 2 to 20; R_(e) and R_(f) are each        independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a        hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic        ring, an alkylaryl, a cycloalkylalkyl, a heterocyclicalkyl, an        alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino,        an arylamino, a diarylamino, an alkylarylamino, an        alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, a sulfonic        ester, an alkylsulfonic acid, an arylsulfonic acid, an        arylalkoxy, an alkylthio, an arylthio, a cycloalkylthio, a        cycloalkenyl, a cyano, an aminoalkyl, an aminoaryl, an aryl, an        arylalkyl, an alkylaryl, a carboxamido, a alkylcarboxamido, an        arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an        alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbonyl,        an arylcarbonyl, an ester, a carboxylic ester, an        alkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, a        sulfonamido, an alkylsulfonamido, an arylsulfonamido, a sulfonic        ester, a urea, a phosphoryl, a nitro, -T-Q , or        (C(R_(e))(R_(f)))_(k)-T-Q, or R_(e) and R_(f) taken together        with the carbons to which they are attached form a carbonyl, a        methanthial, a heterocyclic ring, a cycloalkyl group or a        bridged cycloalkyl group; Q is —NO or —NO₂; and T is        independently a covalent bond, a carbonyl, an oxygen, —S(O)_(o)—        or —N(R_(a))R_(i)—, wherein o is an integer from 0 to 2, R_(a)        is a lone pair of electrons, a hydrogen or an alkyl group; R_(i)        is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an        aryl carboxylic acid, an alkylcarboxylic ester, an        arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido,        an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an        arylsulfinyl, an arylsulfonyl, a sulfonamido, a carboxamido, a        carboxylic ester, an amino alkyl, an amino aryl,        —CH₂—C(T-Q)(R_(e))(R_(f)), or —(N₂O₂—)⁻.M⁺, wherein M⁺ is an        organic or inorganic cation; with the proviso that when R_(i) is        —CH₂—C(T-Q)(R_(e))(R_(f)) or —(N₂O₂—).M⁺; then “-T-Q” can be a        hydrogen, an alkyl group, an alkoxyalkyl group, an aminoalkyl        group, a hydroxy group or an aryl group.

In cases where R_(e) and R_(f) are a heterocyclic ring or taken togetherR_(e) and R_(f) are a heterocyclic ring, then R_(i) can be a substituenton any disubstituted nitrogen contained within the radical wherein R_(i)is as defined herein.

Nitrosothiols can be prepared by various methods of synthesis. Ingeneral, the thiol precursor is prepared first, then converted to theS-nitrosothiol derivative by nitrosation of the thiol group with NaNO₂under acidic conditions (pH is about 2.5) which yields the S-nitrosoderivative. Acids which can be used for this purpose include aqueoussulfuric, acetic and hydrochloric acids. The thiol precursor can also benitrosylated by reaction with an organic nitrite such as tert-butylnitrite, or a nitrosonium salt such as nitrosonium tetraflurorborate inan inert solvent.

Another group of NO adducts for use in the present invention, where theNO adduct is a compound that donates, transfers or releases nitricoxide, include compounds comprising at least one ON—O—, ON—N— or ON—C—group. The compounds that include at least one ON—O—, ON—N— or ON—C—group are preferably ON—O—, ON—N— or ON—C-polypeptides (the term“polypeptide” includes proteins and polyamino acids that do not possessan ascertained biological function, and derivatives thereof); ON—O,ON—N— or ON—C-amino acids (including natural and synthetic amino acidsand their stereoisomers and racemic mixtures); ON—O—,

ON—N— or ON—C-sugars; ON—O—, ON—N— or ON—C— modified or unmodifiedoligonucleotides (comprising at least 5 nucleotides, preferably 5-200nucleotides); ON—O—, ON—N— or ON—C— straight or branched, saturated orunsaturated, aliphatic or aromatic, substituted or unsubstitutedhydrocarbons; and ON—O—, ON—N— or ON—C-heterocyclic compounds.

Another group of NO adducts for use in the present invention includenitrates that donate, transfer or release nitric oxide, such ascompounds comprising at least one O₂N—O—, O₂N—N—, O₂N—S— or O₂N—C—group. Preferred among these compounds are O₂N—O—, O₂N—N—, O₂N—S— orO₂N—C— polypeptides (the term “polypeptide” includes proteins and alsopolyamino acids that do not possess an ascertained biological function,and derivatives thereof); O₂N—O—, O₂N—N—, O₂N—S— or O₂N—C— amino acids(including natural and synthetic amino acids and their stereoisomers andracemic mixtures); O₂N—O—, O₂N—N—, O₂N—S— or O₂N—C-sugars; O₂N—O—,O₂N—N—, O₂N—S— or O₂N—C— modified and unmodified oligonucleotides(comprising at least 5 nucleotides, preferably 5-200 nucleotides);O₂N—O—, O₂N—N—, O₂N—S— or O₂N—C— straight or branched, saturated orunsaturated, aliphatic or aromatic, substituted or unsubstitutedhydrocarbons; and O₂N—O—, O₂N—N—, O₂N—S— or O₂N—C— heterocycliccompounds. Preferred examples of compounds comprising at least oneO₂N—O—, O₂N—N—, O₂N—S— or O₂N—C— group include isosorbide dinitrate,isosorbide mononitrate, clonitrate, erythrityltetranitrate, mannitolhexanitrate, nitroglycerin, pentaerythritoltetranitrate, pentrinitroland propatylnitrate.

Another group of NO adducts are N-oxo-N-nitrosoamines that donate,transfer or release nitric oxide and are represented by the formula:R¹R²N—N(O-M⁺)-NO, where R¹ and R²are each independently a polypeptide,an amino acid, a sugar, a modified or unmodified oligonucleotide, astraight or branched, saturated or unsaturated, aliphatic or aromatic,substituted or unsubstituted hydrocarbon, or a heterocyclic group, andwhere M⁺ is an organic or inorganic cation, such as, for example, analkyl substituted ammonium cation or a Group I metal cation.

Another group of NO adducts are thionitrates that donate, transfer orrelease nitric oxide and are represented by the formula: R¹—(S)—NO₂,where R¹ is a polypeptide, an amino acid, a sugar, a modified orunmodified oligonucleotide, a straight or branched, saturated orunsaturated, aliphatic or aromatic, substituted or unsubstitutedhydrocarbon, or a heterocyclic group. Preferred are those compoundswhere R¹ is a polypeptide or hydrocarbon with a pair or pairs of thiolsthat are sufficiently structurally proximate, i.e., vicinal, that thepair of thiols will be reduced to a disulfide. Compounds which formdisulfide species release nitroxyl ion (NO—) and uncharged nitric oxide(NO.). Compounds where the thiol groups are not sufficiently close toform disulfide bridges generally provide nitric oxide as the NO— formand not as the uncharged NO. form.

The present invention is also directed to compounds that stimulateendogenous NO or elevate levels of endogenous endothelium-derivedrelaxing factor (EDRF) in vivo or are substrates for the enzyme, nitricoxide synthase. Such compounds include, for example, L-arginine,L-homoarginine, and N-hydroxy-L-arginine, including their nitrosated andnitrosylated analogs (e.g., nitrosated L-arginine, nitrosylatedL-arginine, nitrosated N-hydroxy-L-arginine, nitrosylatedN-hydroxy-L-arginine, nitrosated L-homoarginine and nitrosylatedL-homoarginine), precursors of L-arginine and/or physiologicallyacceptable salts thereof, including, for example, citrulline, ornithine,glutamine, lysine, polypeptides comprising at least one of these aminoacids, inhibitors of the enzyme arginase (e.g., N-hydroxy-L-arginine and2(S)-amino-6-boronohexanoic acid) and the substrates for nitric oxidesynthase, cytokines, adenosin, bradykinin, calreticulin, bisacodyl, andphenolphthalein. EDRF is a vascular relaxing factor secreted by theendothelium, and has been identified as nitric oxide (NO) or a closelyrelated derivative thereof (Palmer et al, Nature, 327:524-526 (1987);Ignarro et al, Proc. Natl. Acad. Sci. USA, 84:9265-9269 (1987)).

Another aspect of the invention provides methods for preventing and/ortreating gastrointestinal disorders by administering to the patient inneed thereof a therapeutically effective amount of the compounds and/orcompositions described herein. Such gastrointestinal disorders include,for example, inflammatory bowel disease, Crohn's disease, irritablebowel syndrome, ulcerative colitis, peptic ulcers, stress ulcers,bleeding peptic ulcers, duodenal ulcers, infectious enteritis, colitis,diverticulitis, gastric hyperacidity, dyspepsia, gastroparesis,Zollinger-Ellison syndrome, gastroesophageal reflux disease,Helicobacter Pylori associated disease, short-bowel (anastomosis)syndrome, hypersecretory states associated with systemic mastocytosis orbasophilic leukemia and hyperhistaminemia that result, for example, fromneurosurgery, head injury, severe body trauma or burns. In one aspect ofthe invention, the patient can be administered at least one nitrosatedand/or nitrosylated proton pump inhibitor of the invention to preventand/or treat the gastrointestinal disorder. In another aspect of theinvention, the patient can be administered at least one antacid and atleast one nitrosated and/or nitrosylated proton pump inhibitor of theinvention to prevent or treat the gastrointestinal disorder. In anotheraspect of the invention, the patient can be administered at least onenitrosated and/or nitrosylated proton pump inhibitor of the inventionand at least one compound that donates, transfers or releases nitricoxide, or elevates endogenous levels of nitric oxide or EDRF, or is asubstrate for nitric oxide synthase, to prevent and/or treat thegastrointestinal disorder. In still another aspect of the invention, thepatient can be administered at least one antacid, at least onenitrosated and/or nitrosylated proton pump inhibitor of the invention,and at least one compound that donates, transfers or releases nitricoxide, or elevates endogenous levels of nitric oxide or EDRF, or is asubstrate for nitric oxide synthase, to prevent and/or treat thegastrointestinal disorder. In yet another aspect of the presentinvention, the patient can be administered at least one proton pumpinhibitor and at least one compound that donates, transfers or releasesnitric oxide, or elevates endogenous levels of nitric oxide or EDRF, oris a substrate for nitric oxide synthase, to prevent and/or treat thegastrointestinal disorder. In yet another aspect of the presentinvention, the patient can be administered at least one antacid, atleast one proton pump inhibitor, and at least one compound that donates,transfers or releases nitric oxide, or elevates endogenous levels ofnitric oxide or EDRF, or is a substrate for nitric oxide synthase, toprevent and/or treat the gastrointestinal disorder.

The antacid, proton pump inhibitor that is optionally substituted withat least one NO and/or NO₂ group, and/or the nitric oxide donor can beadministered separately or as components of the same composition. Thesecompounds and/or compositions can also be provided in the form of apharmaceutical kit. The proton pump inhibitors substituted with at leastone NO and/or NO₂ group and preferred nitric oxide donors are describedin detail herein. Appropriate antacids for use in this aspect of theinvention include any antacid known in the art, including, for example,aluminum hydroxide, magnesium hydroxide, magnesium carbonate, calciumcarbonate and co-dried gels, such as, for example, aluminumhydroxide-magnesium carbonate co-dried gel.

Another aspect of the present invention provides methods to improve thegastroprotective properties, anti-Helicobacter properties and antacidproperties of proton pump inhibitors by administering to a patient inneed thereof a therapeutically effective amount of the compounds and/orcompositions described herein. In one aspect of the invention, thepatient can be administered at least one nitrosated and/or nitrosylatedproton pump inhibitor of the invention to improve the gastroprotectiveproperties, anti-Helicobacter properties and antacid properties of theproton pump inhibitor. In another aspect of the invention, the patientcan be administered a bismuth-complex comprising at least one nitrosatedand/or nitrosylated proton pump inhibitor of the invention to improvethe gastroprotective properties, anti-Helicobacter properties andantacid properties of the proton pump inhibitor. In another aspect ofthe invention, the patient can be administered at least one nitrosatedand/or nitrosylated proton pump inhibitor of the invention and at leastone compound that donates, transfers or releases nitric oxide, orelevates endogenous levels of nitric oxide or EDRF, or is a substratefor nitric oxide synthase, to improve the gastroprotective properties,anti-Helicobacter properties and antacid properties of the proton pumpinhibitor. In another aspect of the invention, the patient can beadministered a bismuth complex comprising at least one nitrosated and/ornitrosylated proton pump inhibitor of the invention and at least onecompound that donates, transfers or releases nitric oxide, or elevatesendogenous levels of nitric oxide or EDRF, or is a substrate for nitricoxide synthase, to improve the gastroprotective properties,anti-Helicobacter properties and antacid properties of the proton pumpinhibitor. In yet another aspect of the invention, the patient can beadministered at least one proton pump inhibitor and at least onecompound that donates, transfers or releases nitric oxide, or elevatesendogenous levels of nitric oxide or EDRF, or is a substrate for nitricoxide synthase, to improve the gastroprotective properties,anti-Helicobacter properties and antacid properties of the proton pumpinhibitor. In yet another aspect of the present invention, the patientcan be administered a bismuth-complex comprising at least one protonpump inhibitor and at least one compound that donates, transfers orreleases nitric oxide, or elevates endogenous levels of nitric oxide orEDRF, or is a substrate for nitric oxide synthase, to improve thegastroprotective properties, anti-Helicobacter properties and antacidproperties of the proton pump inhibitor.

The bismuth-containing reagent, proton pump inhibitor, that isoptionally, substituted with at least one NO and/or NO₂ group, and/ornitric oxide donor can be administered separately or as components ofthe same composition. The proton pump inhibitors, optionally substitutedwith at least one NO and/or NO₂ group, and nitric oxide donors aredescribed in detail herein. Bismuth complexes are prepared by boilingthe aqueous solution of the free base of the proton pump inhibitor withat least one bismuth-containing reagent, including, for example, bismuthcitrate, bismuth salicylate, bismuth tartaric acid or mixtures thereofas described in U.S. Pat. No. 5,403,830 and in Ivanov et al, J. Pharm.Pharmacol., 48:297-301 (1996), the disclosures of which are incorporatedby reference herein in their entirety.

Another aspect of the present invention provides methods to facilitateulcer healing and decrease the recurrence of ulcers by administering toa patient in need thereof a therapeutically effective amount of thecompounds and/or compositions described herein. In one aspect of theinvention, the patient can be administered at least one nitrosatedand/or nitrosylated proton pump inhibitor of the invention to facilitateulcer healing and decrease the recurrence of ulcers. In another aspectof the invention, the patient can be administered at least onenitrosated and/or nitrosylated proton pump inhibitor of the inventionand at least one compound that donates, transfers or releases nitricoxide, or elevates endogenous levels of nitric oxide or EDRF, or is asubstrate for nitric oxide synthase to facilitate ulcer healing anddecrease the recurrence of ulcers. In yet another aspect of theinvention, the patient can be administered at least one proton pumpinhibitor and at least one compound that donates, transfers or releasesnitric oxide, or elevates endogenous levels of nitric oxide or EDRF, oris a substrate for nitric oxide synthase, to facilitate ulcer healingand decrease the recurrence of ulcers. The proton pump inhibitor, thatis optionally, substituted with at least one NO and/or NO₂ group, and/ornitric oxide donor can be administered separately or as components ofthe same composition. The proton pump inhibitor, optionally substitutedwith at least one NO and/or NO₂ group, and nitric oxide donors aredescribed in detail herein.

Another aspect of the present invention provides methods to decrease orreverse gastrointestinal toxicity and facilitate ulcer healing resultingfrom, for example, the administration of nonsteroidal antiinflammatorydrugs (NSAIDs), selective COX-2 inhibitors, and the like. In particular,the present invention provides methods of administering atherapeutically effective amount of the compounds and/or compositionsdescribed herein, and, optionally, administering a therapeuticallyeffective amount of at least one NSAID or selective COX-2 inhibitor. Inone aspect of the invention, the patient can be administered at leastone nitrosated and/or nitrosylated proton pump inhibitor of theinvention, and, optionally, at least one NSAID and/or selective COX-2inhibitor, to decrease or reverse gastrointestinal toxicity and/or tofacilitate ulcer healing resulting from the NSAID and/or selective COX-2inhibitor treatment. In another aspect of the invention, the patient canbe administered at least one NSAID and/or selective COX-2 inhibitor witha therapeutically effective amount of at least one nitrosated and/ornitrosylated proton pump inhibitor of the invention and at least onecompound that donates, transfers or releases nitric oxide, or elevatesendogenous levels of nitric oxide or EDRF, or is a substrate for nitricoxide synthase, to decrease or reverse gastrointestinal toxicity and/orto facilitate ulcer healing resulting from the NSAID and/or selectiveCOX-2 inhibitor treatment. In yet another aspect of the presentinvention, the patient can be administered at least one NSAID and/orselective COX-2 inhibitor with a therapeutically effective amount of atleast one proton pump inhibitor and at least one compound that donates,transfers or releases nitric oxide, or elevates endogenous levels ofnitric oxide or EDRF, or is a substrate for nitric oxide synthase, todecrease or reverse gastrointestinal toxicity and/or to facilitate ulcerhealing resulting from the NSAID and/or selective COX-2 inhibitortreatment. The NSAID and/or selective COX-2 inhibitor, nitrosated and/ornitrosylated proton pump inhibitor, proton pump inhibitor, and/or nitricoxide donor can be administered separately or as components of the samecomposition. These compounds and/or compositions can also be provided inthe form of a pharmaceutical kit.

The compounds and compositions of the present invention can be used inthis aspect of the invention with any NSAID and selective COX-2inhibitor known in the art. Such NSAIDs include, for example, aspirin(e.g., acetylsalicylic acid), salicylate esters and salts, acetateesters of salicylic acid, diflurophenyl derivatives (e.g., diflunisal),salicylsalicylic acids (e.g., salsalate), salts of salicylic acids(e.g., sodium salicylate), salicylamide, sodium thiosalicylate, cholinesalicylate, magnesium salicylate, combinations of choline and magnesiumsalicylates, 5-aminosalicylic acid (e.g., mesalamine),salicylazosulfapyridine (e.g., sulfasalazine), methylsalicylate, and thelike.

Another group of NSAIDs are the pyrazolon derivatives, which include,for example, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine,dipyrone and apazone (azapropazone). Another group of NSAIDs are thepara-aninophenol derivatives, which are the so-called “coal tar”analgesics, including, for example, phenacetin and its active metaboliteacetaminophen. Another group of compounds include indomethacin, amethylated indole derivative, and the structurally related compoundsulindac. Yet another group of compounds is the fenamates which arederivatives of N-phenylanthranilic acid (e.g., mefenarnic, meclofenamic,flufenamic, tolfenamic and etofenamic acids). Another contemplated NSAIDis tolmetin.

Another group of NSAIDs are the propionic acid derivatives. Principalmembers of this group are, for example, ibuprofen, naproxen,flurbiprofen, fenoprofen and ketoprofen. Other members of this groupinclude, for example, fenbufen, pirprofen, oxaprozin, indoprofen andtiaprofenic acid.

Still other NSAIDs are piroxicam, ampiroxicam, oxicam derivatives (whichare a class of antiinflammatory enolic acids), tenoxicam tenidap,diclofenac (one of the series of phenylacetic acid derivatives that havebeen developed as antiinflammatory agents). Other NSAIDs includeetodolac and nabumentone.

Selective COX-2 inhibitors are disclosed in, for example, U.S. Pat. Nos.5,681,842, 5,750,558, 5,756,531, 5,776,984 and in WO 98/39330, WO99/10331 and WO 99/10332 assigned to Abbott Laboratories; and in WO98/50075 assigned to Algos Pharmaceutical Corporation; and in U.S. Pat.No. 5,980,905 assigned to AMBI Inc.; and in U.S. Pat. Nos. 5,776,967,5,824,699, 5,830,911 and in WO 98/04527 and WO 98/21195 assigned toAmerican Home Products Corporation; and in WO 99/18960 assigned to AstraPharmaceuticals Ltd.; and in U.S. Pat. No. 5,905,089 assigned to Boardof Supervisors of Louisiana State University; and in WO 97/13767assigned to Chemisch Pharmazeutische Forschungsgesellschaft MBH; and inWO 96/10021 assigned to The Du Pont Merck Pharmaceutical Company; and inWO 99/13799 assigned to Euro-Celtique; and in U.S. Pat. No. 5,134,142and in WO 99/15505 assigned to Fujisawa Pharmaceutical Co. Ltd.; and inU.S. Pat. Nos. 5,344,991, 5,393,790, 5,521,207, 5,596,008, 5,616,601,5,620,999, 5,633,272, 5,643,933, 5,686,470, 5,696,143, 5,700,816,5,859,257, 5,972,986, 5,990,148 and in WO 94/15932, WO 94/27980, WO95/15316, WO 96/16934, WO 96/25405, WO 96/38418, WO 96/38442, WO96/41645, WO 97/38986, WO 98/06708, WO 98/43649, WO 98/47509, WO98/47890 and WO 99/22720 assigned to G.D. Searle & Co.; and in WO96/31509 and WO 99/12930 assigned to Glaxo Group Limited; and in WO97/34882 assigned to Grupo Farmaceutico Almirall; and in WO 97/03953assigned to Hafslund Nycomed Pharma AG; and in U.S. Pat. No. 5,945,539,5,994,381 and in EP 0 745 596 A1 assigned to Japan Tobacco, Inc.; and inU.S. Pat. No. 5,686,460, 5,807,873 and in WO 97/37984 and WO 99/21585assigned to Laboratoires USPA; and in U.S. Pat. Nos. 5,585,504,5,840,924, 5,883,267, 5,925,631 and in WO 97/44027, WO 97/44028, WO97/45420, WO 98/00416, WO 98/47871, WO 99/15503, WO 99/15513, WO99/20110, WO 99/45913 and WO 99/55830 assigned to Merck & Co. Inc.; andin U.S. Pat. Nos. 5,409,944, 5,436,265, 5,474,995, 5,536,752, 5,550,142,5,510,368, 5,521,213, 5,552,422, 5,604,253, 5,604,260, 5,639,780,5,677,318, 5,691,374, 5,698,584, 5,710,140, 5,733,909, 5,789,413,5,817,700, 5,840,746, 5,849,943, 5,861,419, 5,994,379 and in EP 0 788476 B1, EP 0 863 134 A1 and in WO 94/20480, WO 94/13635, WO 94/26731, WO95/00501, WO 96/19469, WO 96/37467, WO 97/14691, WO 97/16435, WO97/28120, WO 97/28121, WO 97/36863, WO 98/03484, WO 98/43966, WO99/14194, WO 99/14195 and WO 99/23087 assigned to Merck Frosst Canada &Co., and in WO 99/59635 assigned to Merck Sharp & Dohme Limited; and inU.S. Pat. No. 5,380,738 assigned to Monsanto Company; and in WO 99/33796assigned to Nissin Food Products Co. Ltd.; and in U.S. Pat. No.5,783,597 assigned to Ortho Pharmaceutical Corporation; and in WO98/07714 assigned to Oxis International Inc.; and in EP 0 937 722 A1 andin WO 98/50033 and WO 99/05104 assigned to Pfizer Inc.; and in U.S. Pat.No. 5,908,858 assigned to Sankyo Company Limited; and in WO 97/25045assigned to Smithkline Beecham Corporation; and in U.S. Pat. No.5,475,021 assigned to Vanderbilt University; and in WO 99/59634 assignedto Wakamoto Pharmaceutical Co. Ltd., the disclosures of each of whichare incorporated by reference herein in their entirety.

Each of the above NSAIDs and selective COX-2 inhibitors is describedmore fully in the literature, such as in Goodman and Gilman, ThePharmacological Basis of Therapeutics (8th Edition), McGraw-Hill, pages617-657 (1993); Merck Index on CD-ROM, Twelfth Edition, Version 12:1,(1996); STN Express, file phar and file registry, the disclosures ofwhich are incorporated by reference herein in their entirety.

Other NSAIDs and selective COX-2 inhibitors that can be used in thepresent invention include those described in U.S. Pat. No. 5,703,073,and co-pending U.S. application Ser. Nos. 09/441,891 and 60/171,623, thedisclosures of which are incorporated by reference herein in theirentirety.

Another embodiment of the present invention provides methods to treatHelicobacter pylori by administering one or more acid-degradableantibacterial compounds in combination with at least one proton pumpinhibitor that is substituted with at least one NO and/or NO₂ group,and, optionally, a therapeutically effective amount of at least onecompound that donates, transfers or releases nitric oxide and/orstimulates endogenous production of NO or EDRF in vivo. Alternatively,this embodiment provides administering one or more acid-degradableantibacterial compounds in combination with at least one proton pumpinhibitor, and, a therapeutically effective amount of at least onecompound that donates, transfers or releases nitric oxide and/orstimulates endogenous production of NO or EDRF in vivo. U.S. Pat. Nos.5,629,305 and 5,599,794, the disclosures of each of which areincorporated by reference herein in their entirety, disclose treating orpreventing gastrointestinal disorders resulting from Helicobacter pyloriby administering proton pump inhibitors in combination withantibacterial compounds. The proton pump inhibitors increase theintra-gastric pH in the stomach, thereby increasing the bioavailabilityof the acid-labile antibacterial compound. The antibacterialcompound(s), proton pump inhibitor(s), optionally substituted with atleast one NO and/or NO₂ group, and/or nitric oxide donor(s) can beadministered separately, or as components of the same composition. Thecompounds and/or compositions can also be provided in the form of a kit.The proton pump inhibitors that are optionally substituted with at leastone NO group and nitric oxide donors are described herein. Theantibacterial compounds contemplated for use in this embodiment of theinvention include any acid-degradable antibacterial compound that isknown in the art, including, for example antibiotics, such as, forexample, amoxycillin, penicillin, benzylpenicillin, erythromycin base,clarithromycin, and the like.

Yet another embodiment of the present invention provides methods totreat viral infections by administering at least one proton pumpinhibitor that is substituted with at least one NO and/or NO₂ group,and, optionally, a therapeutically effective amount of at least onecompound that donates, transfers or releases nitric oxide and/orstimulates endogenous production of NO or EDRF in vivo. Alternatively,this embodiment provides administering at least one proton pumpinhibitor, and, a therapeutically effective amount of at least onecompound that donates, transfers or releases nitric oxide and/orstimulates endogenous production of NO or EDRF in vivo. U.S. Pat. No.5,945,425, the disclosure of which is incorporated by reference hereinin its entirety, discloses treating viral infections by administeringproton pump inhibitors. The proton pump inhibitor(s), optionallysubstituted with at least one NO and/or NO₂ group, and/or nitric oxidedonor(s) can be administered separately, or as components of the samecomposition. The compounds and/or compositions can also be provided inthe form of a kit. The proton pump inhibitors that are optionallysubstituted with at least one NO group and nitric oxide donors aredescribed herein.

The compounds and compositions of the present invention can beadministered by any available and effective delivery system including,but not limited to, orally, bucally, parenterally, by inhalation spray,by topical application, by injection, transdermally, or rectally (e.g.,by the use of suppositories) in dosage unit formulations containingconventional nontoxic pharmaceutically acceptable carriers, adjuvants,and vehicles, as desired. Parenteral includes subcutaneous injections,intravenous, intramuscular, intrasternal injection, or infusiontechniques.

Transdermal compound administration, which is known to one skilled inthe art, involves the delivery of pharmaceutical compounds viapercutaneous passage of the compound into the systemic circulation ofthe patient. Topical administration can also involve the use oftransdermal administration such as transdermal patches or iontophoresisdevices. Other components can be incorporated into the transdermalpatches as well. For example, compositions and/or transdermal patchescan be formulated with one or more preservatives or bacteriostaticagents including, but not limited to, methyl hydroxybenzoate, propylhydroxybenzoate, chlorocresol, benzalkonium chloride, and the like.Dosage forms for topical administration of the compounds andcompositions can include creams, sprays, lotions, gels, ointments, eyedrops, nose drops, ear drops, and the like. In such dosage forms, thecompositions of the invention can be mixed to form white, smooth,homogeneous, opaque cream or lotion with, for example, benzyl alcohol 1%or 2% (wt/wt) as a preservative, emulsifying wax, glycerin, isopropylpalmitate, lactic acid, purified water and sorbitol solution. Inaddition, the compositions can contain polyethylene glycol 400. They canbe mixed to form ointments with, for example, benzyl alcohol 2% (wt/wt)as preservative, white petrolatum, emulsifying wax, and tenox II(butylated hydroxyanisole, propyl gallate, citric acid, propyleneglycol). Woven pads or rolls of bandaging material, e.g., gauze, can beimpregnated with the compositions in solution, lotion, cream, ointmentor other such form can also be used for topical application. Thecompositions can also be applied topically using a transdermal system,such as one of an acrylic-based polymer adhesive with a resinouscrosslinking agent impregnated with the composition and laminated to animpermeable backing.

Solid dosage forms for oral administration can include capsules,tablets, effervescent tablets, chewable tablets, pills, powders,sachets, granules and gels. In such solid dosage forms, the activecompounds can be admixed with at least one inert diluent such assucrose, lactose or starch. Such dosage forms can also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, effervescent tablets, and pills, the dosage forms can alsocomprise buffering agents. Soft gelatin capsules can be prepared tocontain a mixture of the active compounds or compositions of the presentinvention and vegetable oil. Hard gelatin capsules can contain granulesof the active compound in combination with a solid, pulverulent carriersuch as lactose, saccharose, sorbitol, mannitol, potato starch, cornstarch, amylopectin, cellulose derivatives of gelatin. Tablets and pillscan be prepared with enteric coatings.

Liquid dosage forms for oral administration can include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions can also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

Suppositories for vaginal or rectal administration of the compounds andcompositions of the invention can be prepared by mixing the compounds orcompositions with a suitable nonirritating excipient such as cocoabutter and polyethylene glycols which are solid at room temperature butliquid at body temperature, such that they will melt and release thedrug.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing agents, wetting agents and/or suspendingagents. The sterile injectable preparation can also be a sterileinjectable solution or suspension in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that can be used are water,Ringer's solution, and isotonic sodium chloride solution. Sterile fixedoils are also conventionally used as a solvent or suspending medium.

The compositions of this invention can further include conventionalexcipients, i.e., pharmaceutically acceptable organic or inorganiccarrier substances suitable for parenteral application which do notdeleteriously react with the active compounds. Suitable pharmaceuticallyacceptable carriers include, for example, water, salt solutions,alcohol, vegetable oils, polyethylene glycols, gelatin, lactose,amylose, magnesium stearate, talc, surfactants, silicic acid, viscousparaffin, perfume oil, fatty acid monoglycerides and diglycerides,petroethral fatty acid esters, hydroxymethyl-cellulose,polyvinylpyrrolidone, and the like. The pharmaceutical preparations canbe sterilized and if desired, mixed with auxiliary agents, e.g.,lubricants, preservatives, stabilizers, wetting agents, emulsifiers,salts for influencing osmotic pressure, buffers, colorings, flavoringand/or aromatic substances and the like which do not deleteriously reactwith the active compounds. For parenteral application, particularlysuitable vehicles consist of solutions, preferably oily or aqueoussolutions, as well as suspensions, emulsions, or implants. Aqueoussuspensions may contain substances which increase the viscosity of thesuspension and include, for example, sodium carboxymethyl cellulose,sorbitol and/or dextran. Optionally, the suspension may also containstabilizers.

The composition, if desired, can also contain minor amounts of wettingagents, emulsifying agents and/or pH buffering agents. The compositioncan be a liquid solution, suspension, emulsion, tablet, pill, capsule,sustained release formulation, or powder. The composition can beformulated as a suppository, with traditional binders and carriers suchas triglycerides. Oral formulations can include standard carriers suchas pharmaceutical grades of mannitol, lactose, starch, magnesiumstearate, sodium saccharine, cellulose, magnesium carbonate, and thelike.

Various delivery systems are known and can be used to administer thecompounds or compositions of the present invention, including, forexample, encapsulation in liposomes, microbubbles, emulsions,microparticles, microcapsules and the like. The required dosage can beadministered as a single unit or in a sustained release form

The bioavailabilty of the compositions can be enhanced by micronizationof the formulations using conventional techniques such as grinding,milling, spray drying and the like in the presence of suitableexcipients or agents such as phospholipids or surfactants.

The compounds and compositions of the present invention can beformulated as pharmaceutically acceptable salts. Pharmaceuticallyacceptable salts include, for example, alkali metal salts and additionsalts of free acids or free bases. The nature of the salt is notcritical, provided that it is pharmaceutically-acceptable. Suitablepharmaceutically-acceptable acid addition salts may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsinclude, but are not limited to, hydrochloric, hydrobromic, hydroiodic,nitrous (nitrite salt), nitric (nitrate salt), carbonic, sulfuric,phosphoric acid, and the like. Appropriate organic acids include, butare not limited to, aliphatic, cycloaliphatic, aromatic, heterocyclic,carboxylic and sulfonic classes of organic acids, such as, for example,formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic,tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic,aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic,p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,toluenesulfonic, 2-hydroxyethanesuifonic, sulfanilic, stearic, algenic,β-hydroxybutyric, cyclohexylaminosulfonic, galactaric and galacturonicacid and the like. Suitable pharmaceutically-acceptable base additionsalts include, but are not limited to, metallic salts made fromaluminum, calcium, lithium, magnesium, potassium, sodium and zinc ororganic salts made from primary, secondary and tertiary amines, cyclicamines, N,N′-dibenzylethylenediarnine, chloroprocaine, choline,diethanolamine, ethylenediamine, meglumine (N-methylglucamine) andprocaine and the like. All of these salts may be prepared byconventional means from the corresponding compound by reacting, forexample, the appropriate acid or base with the compound.

“Therapeutically effective amount” refers to the amount of the protonpump inhibitor, that is optionally substituted with at least one NOand/or NO₂ group, nitric oxide donor, antacid, bismuth-complex, NSAID,selective COX-2 inhibitor and/or acid-degradable antibacterial compound,that is effective to achieve its intended purpose. While individualpatient needs may vary, determination of optimal ranges for effectiveamounts of each of the compounds and compositions is within the skill ofthe art. Generally, the dosage required to provide an effective amountof the composition, and which can be adjusted by one of ordinary skillin the art will vary, depending on the age, health, physical condition,sex, weight, extent of the dysfunction of the recipient, frequency oftreatment and the nature and scope of the dysfunction or disease.

The amount of a given proton pump inhibitor, that is optionallysubstituted with at least one NO and/or NO₂ group, which will beeffective in the treatment of a particular disorder or condition willdepend on the nature of the disorder or condition, and can be determinedby standard clinical techniques, including reference to Goodman andGilman, supra; The Physician's Desk R_(e)ference, Medical EconomicsCompany, Inc., Oradell, N.J., 1995; and Drug Facts and Comparisons,Inc., St. Louis, Mo., 1993. The precise dose to be used in theformulation will also depend on the route of administration, and theseriousness of the disease or disorder, and should be decided by thephysician and the patient's circumstances.

The amount of nitric oxide donor in a pharmaceutical composition can bein amounts of about 0.1 to about 10 times the molar equivalent of theproton pump inhibitor. The usual daily doses of proton pump inhibitorsare about 10 mg to about 400 mg per day and the doses of nitric oxidedonors in the pharmaceutical composition can be in amounts of about 1 toabout 500 mg/kg of body weight daily, preferably about 1 to about 50mg/kg of body weight daily. Effective doses may be extrapolated fromdose-response curves derived from in vitro or animal model test systemsand are in the same ranges or less than as described for thecommercially available compounds in the Physician's Desk Reference,supra.

The present invention also provides pharmaceutical kits comprising oneor more containers filled with one or more of the ingredients of thepharmaceutical compounds and/or compositions of the present invention,including, at least, one or more of the proton pump inhibitors, that areoptionally substituted with at least one NO moiety, and one or more ofthe NO donors described herein. Such kits can also include, for example,other compounds and/or compositions (e.g., NSAIDs, antacids and/orantibacterial compounds), a device(s) for administering the compoundsand/or compositions, and written instructions in a form prescribed by agovernmental agency regulating the manufacture, use or sale ofpharmaceuticals or biological products, which instructions can alsoreflect approval by the agency of manufacture, use or sale for humanadministration.

EXAMPLES Example 1{2-[(2-Pyridylmethyl)sulfinyl]benzimidazolyl}methyl-3-{N-[2-methyl-2-(nitrosothio)-propyl]-N-benzylcarbamoyl}propanoate1a. 2-Methyl-1-(benzylamino)propane-2-thiol

A solution of α,α′-dithiodiisobutyraldehyde (10.31 g, 0.05 mol) andbenzylamine (10.71 g, 0.10 mol) in chloroform (150 ml) was heated toreflux for 2 hours. The solution was cooled to room temperature, thechloroform was removed under vacuum and the residue was taken in upmethanol (100 ml). Under ice cooling, sodium borohydride (6 g, 0.16 mol)was then added in portions over 1 hour and the resulting solution wasstirred at room temperature for 1 hour. The reaction was concentratedunder vacuum and the residue was partitioned between water (300 ml) andethyl acetate (50 ml). The aqueous phase was extracted with ethyl ether(2×50 ml) and the combined organic phases were washed with brine anddried (Na₂SO₄). The volatiles were evaporated to give an oil (18.45 g,95%) which was used directly in the next step. ¹H NMR (300 MHz, CDCl₃):δ1.29 (s, 12H), 2.57 (s, 4H), 3.81 (s, 4H), 7.21-7.33 (m, 10H). To asolution of the above oil (13.26 g, 0.034 mol) in ether (70 ml) andliquid ammonia (100 ml) cooled over a dry ice/acetone bath was addedsodium until a blue color persisted for 40 min (˜2 g of sodium wasconsumed). Ammonium chloride (15 g) was added and the reaction mixturewas left overnight at room temperature. Water (100 ml) was added and theether layer was separated. The aqueous phase was extracted with ether(2×50 ml) and the combined ether layers were washed with brine and dried(Na₂SO₄). The solvent was evaporated to give the title compound (12.83g, 96.3%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃): δ1.37 (s, 6H),2.61 (s, 2H), 3.86 (s, 2H), 7.22-7.36 (m, 5H); ¹³C NMR (75 MHz, CDCl₃) δ30.58, 45.43, 54.24, 62.78, 126.86, 127.94, 128.34, 140.64; LCMS (m/e):196 (M+1).

1b. 3-[N-(2-Methyl-2-sulfanylpropyl)-N-benzylcarbamoyl]propanoic acid

To a solution of the product of example 1a (4.52 g, 23.14 mmol) indichloromethane (70 ml) at 0° C. was added succinic anhydride (2.20 g,21.98 mmol). The reaction was stirred at room temperature overnight,washed with water (100 ml), the aqueous phase was extracted withdichloromethane (2×50 ml) and the combined organic phases were washedwith brine and dried (Na₂SO₄). The solvent was evaporated under vacuumand the residue triturated with ether/hexane to give the title compound(6.46 g, 99.5%) as a white solid. mp. 123-126° C.; ¹H NMR (300 MHz,CDCl₃): δ1.40 and 1.47 (2 s, 6H), 1.82 (s, 1H), 2.65-2.86 (m, 4H), 3.47and 3.61 (2s, 2H), 4.89 and 4.93 (2s, 2H), 7.13-7.54 (m, 5H), 10.41 (brs, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 28.21, 29.39, 31.27, 46.43, 53.01,58.51, 125.86, 127.50, 128.96, 136.52, 173.49, 177.63; LCMS (m/e): 296(M+1).

1c. 3-{N-[2-Methyl-2-(nitrosothio)propyl)-N-benzylcarbamoyl]propanoicacid

To a solution of the product of example 1b (4.46 g, 15.1 mmol) indichloromethane (100 ml) at 0° C. was added dropwise t-butyl nitrite(1.94 ml, 16.6 mmol). The resulting green solution was left at roomtemperature for 1 hour. The solvent was evaporated and hexane (20 ml)was added to the residue. The mixture was stored at −20° C. for 1 hour,then the hexane was decanted and the solid dried under vacuum to givepure the title compound (4.46 g, 91.1%) as green crystals. mp. 95-98°C.; ¹H NMR (300 MHz, CDCl₃): δ1.91 and 1.98 (2s, 6H), 2.63-2.78 (m, 4H),4.07 and 4.19 (2 s, 2H), 4.60 and 4.80 (2 s, 2H), 7.06-7.37 (m, 5H); ¹³CNMR (75 MHz, CDCl₃): δ 27.65, 28.26, 29.33, 53.04, 55.74, 58.50, 125.96,127.75, 129.07, 136.06, 173.81, 177.64; LCMS (m/e): 325 (M+1).

1d.{2-[(2-Pyridylmethyl)sulfinyl]benzimidazolyl}methyl-3-{N-[2-methyl-2-(nitrosothio)-propyl]-N-benzylcarbamoyl}propanoate

A mixture of timoprazole (0.51 g, 1.98 mmol) and 37% formaldehyde (0.80ml) in acetonitrile (5 ml) was heated at 70° C. for 15 min. The reactionwas evaporated to give a solid that was washed twice with ethylether/ethyl acetate (4:1) and dissolved in dichloromethane (10 ml). Tothis solution was added Example 1c (0.65 g, 2 mol),4-(N—N-dimethylamino)pyridine (10 mg) and dicyclohexylcarbodiimide (1Min dichloromethane, 4 ml, 4 mmol). After stirring at room temperaturefor 3 hours, the reaction was concentrated under vacuum and the residuewas purified by flash column chromatography (ethyl acetate/hexane, 4:1to 7:1) to afford the title compound (0.65 g, 54.7%) as a green foam. ¹HNMR (300 MHz, CDCl₃): δ1.82 and 1.91 (2 s, 6H), 2.63 and 2.75 (2br s,4H), 4.08 and 4.13 (2 s, 2H), 4.70 and 4.85 (2 s, 2H), 4.88 (d, J=14 Hz,1 H), 4.92 (d, J=14 Hz, 1H), 6.36 (d, J=11.4 Hz, 1H), 6.42 (d, J=11.4Hz, 1H), 7.00 and 7.06(2 d, J=6.8Hz, 2H), 7.20-7.64 (m, 9H), 7.81 (d,J=7.7Hz, 1H), 8.54 (d, J=4 Hz, 1 H); ¹³C NMR (75 MHz, CDCl₃): δ27.29,27.94, 28.88, 52.58, 55.29, 58.18, 62.22, 65.04, 110.73, 120.73, 122.97,123.85, 125.21, 125.30, 125.58, 127.41, 128.76, 135.03, 135.79, 136.66,141.70, 149.71, 150.20, 151.66, 171.80, 172.76; LCMS (m/e): 594 (M+1).

Example 2{2-({[3-Methyl-4-(2,2,2-trifluoroethyl)-2-pyridyl]methyl}sulfinyl)benzimidazolyl]-methyl-3-{N-[2-methyl-2-(nitrosothio)-propyl]-N-benzylcarbamoyl}propanoate2a{2-({[3-Methyl-4-(2,2,2-trifluoroethyl)-2-pyridyl]methyl}sulfinyl)benzimidazol]-methyl-3-{N-[2-methyl-2-(nitrosothio)-propyl]-N-benzylcarbamoyl}propanoate

The procedure described in Example 1d was repeated using lansoprozole(0.739 g, 2 mmol) instead of timoprazole. The title compound (0.82 g,59.4%) was obtained as a green foam. ¹H NMR (300 MHz, CDCl₃): δ1.84 and1.92 (2 s, 6H), 2.28 (s, 3H), 2.65 and 2.76 (2 br s,4H), 4.01 and 4.10(2s, 2H), 4.39 (q, J=7.3 Hz, 2H), 4.56 and 4.72(2 s, 2H), 4.96 (d, J=14Hz, 1H), 5.03 (d, J=14 Hz, 1H), 6.46 (d, J=11 Hz, 1H), 6.54 (d, J=11 Hz,1H), 6.65 (d, J=5 Hz, 1H), 7.00-7.40 (m, 7H), 7.64 (d, J=7.4 Hz, 1H),7.80 (d, J=7.5 Hz, 1H), 8.25 (d, J=5 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃):δ24.85, 27.47, 28.13, 29.11, 33.82, 52.80, 55.53, 58.37, 59.81, 65.26(q, J=36 Hz), 65.36, 105.81, 110.85, 120.93, 122.97, 123.92, 125.28,125.78, 127.58, 128.93, 135.21, 136.01, 141.97, 148.09, 151.30, 152.81,161.67, 171.96, 172.95; LCMS (m/e): 690 (M+1).

Example 3 2-[2-(Nitrosothio)adamantan-2-yl]ethyl2-({[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl}sulfinyl)benzimidazolecarboxylate3a. Adamantane-2-thione

Adamantan-2-one (48.46 g, 322.6 mmol) in pyridine (300 mL) was heated to90° C. and phosphorous pentasulfide (17.84 g, 40.13 mmol) was added. Thereaction was maintained at 90° C. for two hours and at room temperatureovernight during which time a precipitate formed. The pyridine solutionwas decanted and concentrated to dryness. The residual semisolid wastreated with hexane (400 mL) to give an orange solution with a lightbrown suspension. The suspension was removed by filtration. The filtratewas concentrated to dryness and dried to vacuum to give an orange solid(50.36 g). This crude product was purified by filtration through a padof silica gel (hexane). ¹H NMR (CDCl₃, 300 MHz): δ3.43 (s, 2H), 2.1-1.9(m, 12H); ¹³C NMR (75 MHz, CDCl₃): δ 222.4, 57.5, 41.1, 36.5, 27.4.

3b. tert-Butyl 2-(2-sulfanyladamantan-2-yl)acetate

To t-butyl acetate (25 mL, 21.6 g, 186 mmol) in dry THF (400 mL) at −78°C. was added lithium diisopropylamide monotetrahydrofuran (1.5M solutionin cyclohexane, 100 mL, 150 mmol) under nitrogen and the reactionmixture was stirred at −78° C. for 40 minutes. The product of Example 3a(21.88 g, 131.57 mmol) in THF (400 mL) was added. The cold bath wasremoved and the reaction was stirred at room temperature for two hours.The reaction was diluted with methylene chloride and 2M HCl (75 mL) wasadded. The organic phase was separated, washed with brine (4×40 mL),dried (MgSO₄), filtered, and concentrated. The crude product waspurified by filtration through a pad of silica gel (5% EtOAc/95% hexane)to give the title compound (34.67 g, 122.7 mmol, 93%). Rf=0.48(EtOAc/hexane 1:19); ¹H NMR (CDCl₃, 300 MHz): δ2.87 (s, 2H), 2,47 (d,J=11.5, 2H), 2.38 (s, 1H), 2.11 (d, J=11.9, 2H), 1.98 (s, 2H), 1.96 (m,2H), 1.84-1.62 96 (m, 6H), 1.47 (s, 9H); ¹³C NMR (75 MHz, CDCl₃):δ170.8, 80.7, 54.1, 47.3, 39.0, 38.2, 37.2, 36.6, 34.0, 33.3, 28.2,27.5, 26.9. APIMS (IS, NH₄OAc) m/e 283 (MH⁺); Anal. Caled for C₁₆H₂₆O₂S(282.44): C, 68.04; H, 9.28 Found: C, 68.14; H, 9.30.

3c. 2-(2-Sulfanyladamantan-2-yl)ethan-1-ol

To a 0° C. cooled solution of Example 3b (4.1 g, 24.1 mmol) in anhydrousdichloromethane (40 mL) lithium aluminum hydride (1M solution in THF)(40 mL) was added dropwise over a period of 20 minutes. The reactionmixture was stirred at 0° C. for further 15 minutes and then at roomtemperature for 30 minutes. The excess LiAIH₄ was destroyed by theaddition of ethyl acetate. The reaction mixture was then poured over icecold water, acidified with 1N HCl and extracted with dichloromethane(2×200 mL). The combined extracts were washed with brine (1×75 mL),dried over sodium sulfate, filtered and solvent evaporated at reducedpressure to give the title compound (3.1 g), mp 68-70° C.; ¹H NMR(CDCl₃): δ1.16-1.9 (m, 1H), 2.1 (m, 2H), 2.22 (t, J=6.9Hz, 3H), 2.43 (m,2H), 3.93 (t, J=6.9 Hz, 2H); ¹³C NMR (CDCl₃): δ 26.8, 27.7, 33.2, 33.9,38.2, 39.1, 43.4, 55.8, 59.4; LRMS (APIMS) (m/z) 230 (M+18) (M+NH₄).

3d. 2-[2-(Nitrosothio)adamantan-2-yl]ethan-1-ol

To a 0° C. cooled solution of Example 3c (1.06 g, 5 mmol) in anhydrousdichloromethane (40 mL) was added t-butyl nitrite (7.5 mmol, 890 μL).The reaction mixture was stirred at 0° C. for 30 minutes and then atroom temperature for 30 minutes. The solvent was removed at reducedpressure and product was recrystallized from ethyl ether/hexane to give1.2 g (80% yield) of the title compound as a green crystalline solid, mp77-79° C.; ¹H NMR (CDCl₃): δ 1.7-1.74 (m, 2H), 1.83-1.93 (m, 5H), 2.06(m, 3H), 2.42-2.53 (m, 4H), 2.99 (t, J=7.3 Hz, 2H), 3.83 (t, J=7.6 Hz,2H); ¹³C NMR (CDCl₃): δ 27.3, 27.4, 33.2, 33.9, 35.6, 38.97, 39.96,59.1, 68.2; LRMS (APIMS) (m/z) 259 (M+18) (M+NH₄).

3e. 2-[2-(Nitrosothio)adamanta-2-yl]ethyl chlorooate

An ice-cooled solution of 20% phosgene in toluene (2.5 ml, 5.4 mmol) wasadded dropwise to a solution of Example 3d (0.41 g, 1.7 mmol) andpyridine (0.138 ml, 1.7 mmol) in dichloromethane (4 ml). After stirringat 0° C. for 20 min, the reaction was concentrated using a rotaryevaporator. To the residue was added dry ether (20 ml). The reactionmixture was filtered, washed with ether (2×5 ml) and the organic layerwas concentrated under vacuum to gave the crude product, which was usedimmediately for next step.

3f.2-[2-(Nitrosothio)adamantan-2-yl]ethyl-2-({[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl}sulfinyl)benzimidazolecarboxylate

Lansoprazole (0.50 g, 1.35 mmol) was added to a suspension of sodiumhydride (39 mg, 1.63 mmol) in N,N-dimethylformamide (3 ml) at roomtemperature. The resulting clear solution was cooled in an ice bath. Asolution of Example 3e in N,N-dimethylformamide (3 ml) was then added.After stirring at 0° C. for 30 min, the reaction mixture was dilutedwith ethyl ether/ethyl acetate (3:2 v/v) (70 ml) and washed with water(2×30 ml) and then brine (20 ml). The combined organic extracts weredried over Na₂SO₄ and evaporated under vacuum. The residue was purifiedby flash chromatography (SiO₂, 4/1 to 3/1 dichloromethane/acetone) togive the title compound as a green solid (0.52 g, 60.3%). Mp. 125-130°C. (dec.)(at 116° C. it started to shrink). ¹H NMR (300 MHz, CDCl₃)δ8.06 (d, J=5.6 Hz, 1H), 7.90 (d, J=7.5 Hz, 1H), 7.82 (d, J=7.7 Hz, 1H),7.48-7.38 (m, 2H), 6.56 (d, J=5.6 Hz, 1H), 4.78 (d, J=13 Hz, 1H), 4.75(t, J=7.8 Hz, 2H), 4.67 (d, J=13 Hz, 1H), 4.37 (q, J=7.8 Hz, 2H), 3.37(t, J=7.8 Hz, 2H), 2.60-2.46 (m, 4H), 2.35 (s, 3H), 2.17-1.76 (m, 10H);¹³C NMR (75 MHz, CDCl₃) δ 161.74, 156.92, 151.19, 149.65, 147.94,142.77, 133.54, 126.50, 125.24, 124.55, 121.38, 114.61, 105.66, 67.04,65.88, 65.36 (q, J=36 Hz), 59.45, 38.74, 35.68, 35.58, 35.52, 33.73,33.10, 33.08, 27.26, 27.11, 11.37; MS (m/e): 637 (M+1).

Example 4 Comparative In Vivo Gastric Lesion Activity

The ethanol/HCl mixture-induced gastric lesion test in rats described byTakeuchi et al, J. Pharmacol. Exp. Ther., 286: 115-121 (1998), was usedto evaluate gastric lesion activity. Male Sprague Dawley rats (CharlesRiver Laboratories, Wilmington, Ma.) weighing 230-250 g were used forthe experiments. The rats were housed with laboratory chow and water adlibitum prior to the study. The rats were fasted for 24 hours with freeaccess to water and then dosed by oral gavage with vehicle or with thetest compounds given at a volume of 0.5 ml/100 g body weight. Thirtyminutes after oral dosing all the rats received 1 ml of a solution of60% ethanol in 150 mM HCl intragastrically. Food was withheld afterdosing. Sixty minutes after ethanol/HCl, rats were euthanized bypre-charged CO₂. The stomachs were dissected along the greatercurvature, washed with a directed stream of 0.9% saline and pinned openon a sylgard based petri dish for examination of the hemorrhagiclesions. Gastric lesion score was expressed in mm and calculated bysumming the length of each lesion as described by Al-Ghamdi et al, J.Int. Med. Res., 19:2242 (1991). Results are expressed as the mean ±standard error of the mean. Statistical analysis were conducted usingANOVA test followed by a Student-Newman-Keuls post-hoc test using theAbacus Concepts, Super Anova computer program (Abacus Concepts, Inc.,Berkeley, Calif.).

FIG. 1 compares the gastric lesion activity of vehicle alone,lanzoprazole in vehicle and Example 2 (nitrosylated lanzoprazole) invehicle. Ethanol/HCl mixture produced gastric lesion in the control ratstreated with vehicle (0.5% Methocel). Lanzoprazole at a dose of 200μmol/kg failed to significantly inhibit the formation of gastriclesions. The nitrosylated lanzoprazole derivative of Example 2, at 200μmol/kg, significantly inhibited the formation of gastric lesionsproduced by the ethanol/HCl mixture.

The disclosure of each patent, patent application and publication citedor described in the present specification is hereby incorporated byreference herein in its entirety.

Although the invention has been set forth in detail, one skilled in theart will appreciate that numerous changes and modifications can be madeto the invention, and that such changes and modifications can be madewithout departing from the spirit and scope of the present invention.

1. A proton pump inhibitor compound of formula (I), or apharmaceutically acceptable salt thereof, having at least one NO group,at least one NO₂ group, or at least one NO and NO₂ group; wherein the atleast one NO group, the at least one NO₂ group, or the at least one NOand NO₂ group is linked to the proton pump inhibitor compound through anoxygen atom, a nitrogen atom or a sulfur atom: wherein the compound offormula (I) is:

wherein A is S, S(O), or S(O)₂; B is —CNR₇R₇′ or nitrogen; J is CH ornitrogen; R₁ is a hydrogen, an alkoxy group, a lower alkyl group, or analkylthio group; R₂ is a hydrogen, an alkoxy group, a lower alkyl group,an alkylthio group, a haloalkoxy group, an alkoxyalkyl group, —NR₇R₇′,—OD₁, or SD₁; or R₂ and R₁ taken together with the carbon chain to whichthey are attached form a cycloalkyl ring or a heterocyclic ring; or R₂and R₃ taken together with the carbon chain to which they are attachedform a cycloalkyl ring or a heterocyclic ring; R₃ and R₁₁ are eachindependently a hydrogen, an alkoxy group, a lower alkyl group, or analkylthio group; or R₃ and R₁₁ taken together with the carbon chain towhich they are attached form a cycloalkyl ring or a heterocyclic ring;R₄ and R₅ are each independently a hydrogen, an alkyl group, a halogroup, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyanogroup, an aryl group, a heterocyclic ring, —NR₇R₇′, —OD₁, or —CO₂R₁₂; orR₄ and R₅ taken together are:

wherein R₆ is oxygen or N═O—R₇; R₇ and R₇′ are each independentlyhydrogen, a lower alkyl group or D; or R₇ and R₇′ taken together withthe nitrogen to which they are attached form a heterocyclic ring; R₁₀ isa hydrogen; or R₁₀ and R₁ taken together with the carbon chain to whichthey are attached form a cycloalkyl ring; R₁₂ is a lower alkyl group orD; D₁ is a hydrogen or D; D is Q or K; Q is —NO or —NO₂; K is—W_(a)-E_(b)—(C(R_(e))(R_(f)))_(p)-E_(c)—(C(R_(e))(R_(f)))_(x)—W_(d)—(C(R_(e))(R_(f)))_(y)—W_(i)-E_(j)—W_(g)—(C(R_(e))(R_(f)))_(z)-T-Q;a, b, c, d, g, i and j are each independently an integer from 0 to 3; p,x, y and z are each independently an integer from 0 to 10; W at eachoccurrence is independently —C(O)—, —C(S)—, -T-, —(C(R_(e))(R_(f)))_(h),an alkyl group, an aryl group, a heterocyclic ring, an arylheterocyclicring, or —(CH₂CH₂O)_(q)—; E at each occurrence is independently -T-, analkyl group, an aryl group, —(C(R_(e))(R_(f)))_(h), a heterocyclic ring,an arylheterocyclic ring, or —(CH₂CH₂O)_(q)—; h is an integer form 1 to10; q is an integer from 1 to 5; R_(e) and R_(f) are each independentlya hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, anhydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, acycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino,an alkylamino, a dialkylamino, an arylamino, a diarylamino, analkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, asulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, anarylalkoxy, an alkylthio, an arylthio, a cycloalkylthio, a cycloalkenyl,a cyano, an aminoalkyl, an aminoaryl, an aryl, an arylalkyl, analkylaryl, a carboxamido, a alkylcarboxamido, an arylcarboxamido, anamidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, anarylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, an ester, acarboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, ahaloalkoxy, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, asulfonic ester, a urea, a phosphoryl, a nitro, -T-Q, or(C(R_(e))(R_(f)))_(k)-T-Q, or R_(e) and R_(f) taken together with thecarbon atoms to which they are attached form a carbonyl, a methanthial,a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group; kis an integer from 1 to 3; T at each occurrence is independently acovalent bond, a carbonyl, an oxygen, —S(O)_(o)—or —N(R_(a))R_(i); o isan integer from 0 to 2; R_(a) is a lone pair of electrons, a hydrogen oran alkyl group; R_(i) is a hydrogen, an alkyl, an aryl, analkylcarboxylic acid, an arylcarboxylic acid, an alkylcarboxylic ester,an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido, analkylaryl, an alkylsulfinyl, an alkylsulfonyl, an arylsulfinyl, anarylsulfonyl, a sulfonamido, a carboxamido, a carboxylic ester, an aminoalkyl, an amino aryl, —CH₂—C(T-Q)(R_(e))(R_(f)), or —(N₂O₂—)⁻•M⁺,wherein M⁺ is an organic or inorganic cation; with the proviso that whenR_(i) is —CH₂—C(T-Q)(R_(e))(R_(f)) or —(N₂O₂)⁻•M⁺, or R_(e) or R_(f) areT-Q or (C(R_(e))(R_(f)))_(k)T-Q, then the “-T-Q” subgroup can be ahydrogen, an alkyl, an alkoxy, an alkoxyalkyl, an aminoalkyl, a hydroxy,a heterocyclic ring or an aryl group.
 2. The compound of claim 1,wherein the compound of Formula (I) is a substituted benzimidazole or apharmaceutically acceptable salt thereof; having at least one NO group,at least one NO₂ group, or at least one NO and NO₂ group, wherein the atleast one NO group, the at least one NO₂ group, or the at least one NOand NO₂ group is linked to the proton pump inhibitor compound through anoxygen atom, a nitrogen atom or a sulfur atom.
 3. The compound of claim2, wherein the compound of Formula (I) is omeprazole, lansoprazole,pantoprazole, rabeprazole, leminoprazole, timoprazole, tenatoprazole,disuprazole, esomeprazole, RO 18-5362, or IY 81149; or apharmaceutically acceptable salt thereof having at least one NO group,at least one NO₂ group, or at least one NO and NO₂ group, wherein the atleast one NO group, the at least one NO₂ group, or the at least one NOand NO₂ group is linked to the proton pump inhibitor compound through anoxygen atom, a nitrogen atom or a sulfur atom.
 4. A compound selectedfrom the group consisting of{2-[(2-pyridylmethyl)sulfinyl]benzimidazolyl}methyl-3-{N-[2-methyl-2-(nitrosothio)-propyl]-N-benzylcarbamoyl}propanoate, {2-({[3-methyl-4-(2,2,2-trifluoroethyl)-2-pyridyl]methyl}sulfinylbenzimidazolyl]-methyl-3-{N-[2-methyl-2-(nitrosothio)-propyl]-N-benzylcarbamoyl}propanoate, or 2-[2-(nitrosothio)adamantan-2-yl]ethyl 2-({[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl}sulfinyl)benzimidazolecarboxylate.5. A proton pump inhibitor compound selected from the group consistingof omeprazole, lansoprazole, pantoprazole, rabeprazole, leminoprazole,timoprazole, tenatoprazole, disuprazole and esomeprazole, having atleast one NO group, at least one NO₂ group, or at least one NO and NO₂group, or a pharmaceutically acceptable salt thereof, wherein the atleast one NO group, the at least one NO₂ group, or the at least one NOand NO₂ group is linked to the proton pump inhibitor compound through anoxygen atom, a nitrogen atom or a sulfur atom.
 6. A compositioncomprising the compound of claim 5 or 1 and a pharmaceuticallyacceptable carrier.
 7. The composition of claim 6, further comprising atleast one of a nonsteroidal antiinflammatory drug, a selective COX-2inhibitor, an antacid, a bismuth-containing reagent, and anacid-degradable antibacterial compound.
 8. A composition comprising atleast one compound of claim 5 or 1 or a pharmaceutically acceptable saltthereof, and at least one compound that donates, transfers, or releasesnitric oxide, induces the production of endogenous nitric oxide orendothelium-derived relaxing factor,. stimulates endogenous synthesis ofnitric oxide or is a substrate for nitric oxide synthase.
 9. Thecomposition of claim 8, further comprising a pharmaceutically acceptablecarrier.
 10. The composition of claim 8, wherein the compound thatdonates, transfers, or releases nitric oxide, induces the production ofendogenous nitric oxide or endothelium-derived relaxing factor,stimulates endogenous synthesis of nitric oxide or is a substrate fornitric oxide synthase is an S-nitrosothiol.
 11. The composition of claim10, wherein the S-nitrosothiol is S-nitroso-N-acetylcysteine,S-nitroso-captopril, S-nitroso-N-acetylpenicillamine,S-nitroso-homocysteine, S-nitroso-cysteine or S-nitroso-glutathione. 12.The composition of claim 8, wherein the S-nitrosothiol is: (i)HS(C(R_(e))R_(f))_(m)SNO; (ii) ONS(C(R_(e))(R_(f)))_(m)R_(e); and (iii)H₂N—CH(CO₂H)—(CH₂)_(m)—C(O)NH—CH(CH₂SNO)—C(O)NH—CH₂—CO₂H; wherein m isan integer from 2 to 20; R_(e) and R_(f) are each independently ahydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, anhydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, acycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino,an alkylamino, a dialkylamino, an arylamino, a diarylamino, analkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, asulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, anarylalkoxy, an alkylthio, an arylthio, a cycloalkylthio, a cycloalkenyl,a cyano, an aminoalkyl, an aminoaryl, an aryl, an arylalkyl, analkylaryl, a carboxamido, a alkylcarboxamido, an arylcarboxamido, anamidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, anarylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, an ester, acarboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, ahaloalkoxy, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, asulfonic ester, a urea, a phosphoryl, a nitro, -T-Q , or(C(R_(e))(R_(f)))_(k)-T-Q, or R_(e) and R_(f) taken together with thecarbon atoms to which they are attached form a carbonyl, a methanthial,a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group; Qis —NO or —NO₂; and T is independently a covalent bond, a carbonyl, anoxygen, —S(O)_(o)— or —N(R_(a))R_(i)—, wherein o is an integer from 0 to2, R_(a) is a lone pair of electrons, a hydrogen or an alkyl group;R_(i) is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester, analkylcarboxamido, an arylcarboxamido, an alkylaryl, an alkylsulfinyl, analkylsulfonyl, an arylsulfinyl, an arylsulfonyl, a sulfonamido, acarboxamido, a carboxylic ester, an amino alkyl, an amino aryl,—CH₂—C(T-Q)(R_(e))(R_(f)), or —(N₂O₂—)⁻.M⁺, wherein M⁺is an organic orinorganic cation; with the proviso that when R_(i) is—CH₂—C(T-Q)(R_(e))(R_(f)) or —(N₂O₂—)M³⁰ ; then “-T-Q” can be ahydrogen, an alkyl group, an alkoxyalkyl group, an aminoalkyl group, ahydroxy group or an aryl group.
 13. The composition of claim 8, whereinthe compound that donates, transfers, or releases nitric oxide, inducesthe production of endogenous nitric oxide or endothelium-derivedrelaxing factor, stimulates endogenous synthesis of nitric oxide or is asubstrate for nitric oxide synthase is L-arginine, L-homoarginine,N-hydroxy-L-arginine, nitrosated L-arginine, nitrosylated L-arginine,nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine,citrulline, omithine, glutamine, lysine, polypeptides comprising atleast one of these amino acids or an inhibitor of the enzyme arginase.14. The composition of claim 8, wherein the compound that donates,transfers, or releases nitric oxide, induces the production ofendogenous nitric oxide or endothelium-derived relaxing factor,stimulates endogenous synthesis of nitric oxide or is a substrate fornitric oxide synthase is: (i) a compound that comprises at least oneON—O—, ON—N— or ON—C— group; (ii) a compound that comprises at least oneO₂N—O—, O₂N—N—, O₂N—S— or —O₂N—C— group; (iii) a N-oxo-N-nitrosoaminehaving the formula: R¹R²N—N(O-M³⁰ )—NO, wherein R¹ and R² are eachindependently a polypeptide, an amino acid, a sugar, an oligonucleotide,a straight or branched, saturated or unsaturated, aliphatic or aromatic,substituted or unsubstituted hydrocarbon, or a heterocyclic group, andM⁺is an organic or inorganic cation.
 15. The composition of claim 14,wherein the compound comprising at least one ON—O—, ON—N— or ON—C— groupis an ON—O-polypeptide, an ON-N-polypepetide, an ON—C-polypeptide, anON—O-amino acid, an ON—N-amino acid, an ON—C-amino acid, an ON—O-sugar,an ON—N-sugar, an ON—C-sugar, an ON—O-oligonucleotide, anON—N-oligonucleotide, an ON—C-oligonucleotide, a straight or branched,saturated or unsaturated, substituted or unsubstituted, aliphatic oraromatic ON—O-hydrocarbon, a straight or branched, saturated orunsaturated, substituted or unsubstituted, aliphatic or aromaticON—N-hydrocarbon, a straight or branched, saturated or unsaturated,substituted or unsubstituted, aliphatic or aromatic ON—C-hydrocarbon, anON—O-heterocyclic compound, an ON—N-heterocyclic compound or aON—C-heterocyclic compound.
 16. The composition of claim 14, whereincompound comprising at least one O₂N—O—, O₂N—, O₂N—S— or O₂N—C- group isan O₂N—O-polypeptide, an O₂N—N-polypeptide, an O₂N—S-polypeptide, anO₂N—C-polypeptide, an O₂N—O-amino acid, O₂N—N-amino acid, O₂N—S-aminoacid, an O₂N—C-amino acid, an O₂N—O-sugar, an O₂N—N-sugar, O₂N—S-sugar,an O₂N—C-sugar, an O₂N—O-oligonucleotide, an O₂N—N-oligonucleotide, anO₂N—S-oligonucleotide, an O₂N—C-oligonucleotide, a straight or branched,saturated or unsaturated, aliphatic or aromatic, substituted orunsubstituted O₂N—O-hydrocarbon, a straight or branched, saturated orunsaturated, aliphatic or aromatic, substituted or unsubstitutedO₂N—N-hydrocarbon, a straight or branched, saturated or unsaturated,aliphatic or aromatic, substituted or unsubstituted O₂N—S-hydrocarbon, astraight or branched, saturated or unsaturated, aliphatic or aromatic,substituted or unsubstituted O₂N—C-hydrocarbon, an O₂N—O-heterocycliccompound, an O₂N—N-heterocyclic compound, an O₂N—S-heterocyclic compoundor an O₂N—C-heterocyclic compound.
 17. The composition of claim 16,wherein the compound comprising at least one O₂N—O—, O₂N—N—, O₂N—S— orO₂N—C— group is isosorbide dinitrate, isosorbide mononitrate,clonitrate, erythrityltetranitrate, mannitol hexanitrate, nitroglycerin,pentaerythritoltetranitrate, pentrinitrol and propatylnitrate.
 18. Thecomposition of claim 8, further comprising at least one of anonsteroidal antiinflammatory drug, a selective COX-2 inhibitor, anantacid, a bismuth-containing reagent, and an acid-degradableantibacterial compound.
 19. A method for treating an ulcer in a patientin need thereof comprising administering to the patient atherapeutically effective amount of the composition of claim
 6. 20. Themethod of claim 19, further comprising administering to the patient atherapeutically effective amount of an antacid.
 21. The method of claim19, wherein the ulcer is a peptic ulcer, a stress ulcers, a bleedingpeptic ulcer or a duodenal ulcer.
 22. The method of claim 19, whereinthe composition is administered orally, bucally, topically, byinjection, by inhalation, or by transdermal application.
 23. The methodof claim 22, wherein the composition is administered orally in a soliddosage form or a liquid dosage form.
 24. The method of claim 23, whereinthe solid dosage form is a capsule, a tablet, an effervescent tablet, achewable tablet, a pill, a powder, a sachet, a granule or a gel.
 25. Themethod of claim 23, wherein the liquid dosage form is an emulsion, asolution, a suspension, a syrup, or an elixir.
 26. A method for treatingan ulcer in a patient in need thereof comprising administering to thepatient a therapeutically effective amount of the composition of claim8.
 27. The method of claim 26, further comprising administering to thepatient a therapeutically effective amount of an antacid.
 28. The methodof claim 26, wherein the ulcer is a peptic ulcer, a stress ulcers, ableeding peptic ulcer or a duodenal ulcer.
 29. The method of claim 26,wherein the composition is administered orally, bucally, topically, byinjection, by inhalation, or by transdermal application.
 30. The methodof claim 29, wherein the composition is administered orally in a soliddosage form or a liquid dosage form.
 31. The method of claim 30, whereinthe solid dosage form is a capsule, a tablet, an effervescent tablet, achewable tablet, a pill, a powder, a sachet, a granule or a gel.
 32. Themethod of claim 30, wherein the liquid dosage form is an emulsion, asolution, a suspension, a syrup, or an elixir.
 33. A method for treatingan ulcer in a patient in need thereof comprising administering to thepatient a therapeutically effective amount of the composition of claim 6or a pharmaceutically acceptable salt thereof, and at least one compoundthat donates, transfers, or releases nitric oxide, induces theproduction of endogenous nitric oxide or endothelium-derived relaxingfactor, stimulates endogenous synthesis of nitric oxide or is asubstrate for nitric oxide synthase.
 34. The method of claim 33, furthercomprising administering at least one antacid.
 35. The method of claim33, wherein the ulcer is a peptic ulcer, a stress ulcers, a bleedingpeptic ulcer or a duodenal ulcer.
 36. A kit comprising at least onecompound of claim 5 or a pharmaceutically acceptable salt thereof, andat least one compound that donates, transfers, or releases nitric oxide,induces the production of endogenous nitric oxide or endothelium-derivedrelaxing factor, stimulates endogenous synthesis of nitric oxide or is asubstrate for nitric oxide synthase.
 37. The kit of claim 36, whereinthe at least one compound or a pharmaceutically acceptable salt thereotand the at least one compound that donates, transfers, or releasesnitric oxide, induces the production of endogenous nitric oxide orendothelium-derived relaxing factor, stimulates endogenous synthesis ofnitric oxide or is a substrate for nitric oxide synthase are separatecomponents in the kit or are in the form of a composition in the kit.38. The kit of claim 36, further comprising at least one of anonsteroidal antiinflammatory drug, a selective COX-2 inhibitor, anantacid, a bismuth-containing reagent and an acid-degradableantibacterial compound.
 39. A kit comprising at least one compound ofclaim 1 or a pharmaceutically acceptable salt thereof and at least onecompound that donates, transfers, or releases nitric oxide, induces theproduction of endogenous nitric oxide or endothelium-derived relaxingfactor, stimulates endogenous synthesis of nitric oxide or is asubstrate for nitric oxide synthase.
 40. The kit of claim 39, whereinthe at least one compound or a pharmaceutically acceptable salt thereof,and the at least one compound that donates, transfers, or releasesnitric oxide, induces the production of endogenous nitric oxide orendothelium-derived relaxing factor, stimulates endogenous synthesis ofnitric oxide or is a substrate for nitric oxide synthase are separatecomponents in the kit or are in the form of a composition in the kit.